Kras g12c inhibitors

ABSTRACT

The present invention relates to compounds that inhibit KRas G12C. In particular, the present invention relates to compounds that irreversibly inhibit the activity of KRas G12C, pharmaceutical compositions comprising the compounds and methods of use therefor.

CROSS REFERENCE

This application claims benefit of priority under 35 U.S.C. § 119(e)from U.S. Provisional Application No. 62/338,116, filed May 18, 2016,and U.S. Provisional Application No. 62/444,614 filed Jan. 10, 2017, theentire content of each application is hereby incorporated by referencein their entirety.

FIELD OF THE INVENTION

The present invention relates to compounds that inhibit KRas G12C. Inparticular, the present invention relates to compounds that irreversiblyinhibit the activity of KRas G12C, pharmaceutical compositionscomprising the compounds and methods of use therefor.

BACKGROUND OF THE INVENTION

Kirsten Rat Sarcoma 2 Viral Oncogene Homolog (“KRas”) is a small GTPaseand a member of the Ras family of oncogenes. KRas serves a molecularswitch cycling between inactive (GDP-bound) and active (GTP-bound)states to transduce upstream cellular signals received from multipletyrosine kinases to downstream effectors to regulate a wide variety ofprocesses, including cellular proliferation (e.g., see Alamgeer et al.,(2013) Current Opin Pharmcol. 13:394-401).

The role of activated KRas in malignancy was observed over thirty yearsago (e.g., see Santos et al., (1984) Science 223:661-664). Aberrantexpression of KRas accounts for up to 20% of all cancers and oncogenicKRas mutations that stabilize GTP binding and lead to constitutiveactivation of KRas and downstream signaling have been reported in 25-30%of lung adenocarcinomas. (e.g., see Samatar and Poulikakos (2014) NatRev Drug Disc 13(12): 928-942 doi: 10.1038/nrd428). Single nucleotidesubstitutions that result in missense mutations at codons 12 and 13 ofthe KRas primary amino acid sequence comprise approximately 40% of theseKRas driver mutations in lung adenocarcinoma, with a G12C transversionbeing the most common activating mutation (e.g., see Dogan et al.,(2012) Clin Cancer Res. 18(22):6169-6177, published online 2012 Sep. 26.doi: 10.1158/1078-0432.CCR-11-3265).

The well-known role of KRAs in malignancy and the discovery of thesefrequent mutations in KRas in various tumor types made KRas a highlyattractable target of the pharmaceutical industry for cancer therapy.Notwithstanding thirty years of large scale discovery efforts to developinhibitors of KRas for treating cancer, no KRas inhibitor hasdemonstrated sufficient safety and/or efficacy to obtain regulatoryapproval (e.g., see McCormick (2015) Clin Cancer Res. 21 (8):1797-1801).

Despite many failed efforts to target KRas, compounds that inhibit KRasactivity are still highly desirable and under investigation, includingthose that disrupt effectors such as guanine nucleotide exchange factors(e.g., see Sun et al., (2012) Agnew Chem Int Ed Engl. 51(25):6140-6143doi: 10.1002/anie201201358) as well target KRas G12C (e.g., see Ostremet al., (2013) Nature 503:548-551). Clearly there remains a continuedinterest and effort to develop inhibitors of KRas, particularlyinhibitors of activating KRas mutants, including KRas G12C.

Thus, there is a need to develop new KRas G12C inhibitors thatdemonstrate sufficient efficacy, stability and/or safety for treatingKRas G12C-mediated cancer. The compounds and compositions of the presentinvention advantageously overcome one or more of the previousshortcomings by providing selective KRas G12C inhibitors.

SUMMARY OF THE INVENTION

In one aspect of the invention, compounds are provided that inhibit KRasG12C activity. In certain embodiments, the compounds are represented byformula (I):

or a pharmaceutically acceptable salt thereof, wherein:

X is a 4-12 membered saturated or partially saturated monocyclic,bridged or spirocyclic ring, wherein the saturated or partiallysaturated monocyclic ring is optionally substituted with one or more R⁸

Y is a bond, O, S or NR⁵;

R¹ is —C(O)C(R^(A))

C(R^(B))_(p) or —SO₂C(R^(A))

C(R^(B))_(p);

R² is hydrogen, alkyl, hydroxyalkyl, dihydroxyalkyl, alkylaminylalkyl,dialkylaminylalkyl, —Z—NR⁵R¹⁰, heterocyclyl, heterocyclylalkyl, aryl,heteroaryl, or heteroarylalkyl, wherein each of the Z, heterocyclyl,heterocyclylalkyl, aryl, heteroaryl, and heteroarylalkyl may beoptionally substituted with one or more R⁹;

Z is C1-C4 alkylene;

each R³ is independently C1-C3 alkyl, oxo, or haloalkyl;

L is a bond, —C(O)—, or C1-C3 alkylene;

R⁴ is hydrogen, cycloalkyl, heterocyclyl, aryl, aralkyl or heteroaryl,wherein each of the cycloalkyl, heterocyclyl, aryl, aralkyl andheteroaryl may be optionally substituted with one or more R⁶ or R⁷;

each R⁵ is independently hydrogen or C1-C3 alkyl;

R⁶ is cycloalkyl, heterocyclyl, heterocyclylalkyl, aryl, or heteroaryl,wherein each of the cycloalkyl, heterocyclyl, aryl, or heteroaryl may beoptionally substituted with one or more R⁷;

each R⁷ is independently halogen, hydroxyl, C1-C6 alkyl, cycloalkyl,alkoxy, haloalkyl, amino, cyano, heteroalkyl, hydroxyalkyl orQ-haloalkyl, wherein Q is O or S;

R⁸ is oxo, C1-C3 alkyl, C2-C4 alkynyl, heteroalkyl, cyano, —C(O)OR⁵,—C(O)N(R⁵)₂, —N(R⁵)₂, wherein the C1-C3 alkyl may be optionallysubstituted with cyano, halogen, —OR⁵, —N(R⁵)₂, or heteroaryl

each R⁹ is independently hydrogen, oxo, acyl, hydroxyl, hydroxyalkyl,cyano, halogen, C1-C6 alkyl, aralkyl, haloalkyl, heteroalkyl,cycloalkyl, heterocyclylalkyl, alkoxy, dialkylaminyl, dialkylamidoalkyl,or dialkylaminylalkyl, wherein the C1-C6 alkyl may be optionallysubstituted with cycloalkyl;

each R¹⁰ is independently hydrogen, acyl, C1-C3 alkyl, heteroalkyl orhydroxyalkyl;

R^(A) is absent, hydrogen, or C1-C3 alkyl;

each R^(B) is independently hydrogen, C1-C3 alkyl, alkylaminylalkyl,dialkylaminylalkyl or heterocyclylalkyl;

m is zero or an integer between 1 and 2;

p is one or two; and wherein,

when

is a triple bond then R^(A) is absent, R^(B) is present and p equalsone,

or when

is a double bond then R^(A) is present, R^(B) is present and p equalstwo, or R^(A), R^(B) and the carbon atoms to which they are attachedform a 5-8 membered partially saturated cycloalkyl optionallysubstituted with one or more R⁷.

Also included are compounds of Formula I having the Formula I-A:

wherein R¹, R³, R⁴, R⁵, R¹⁰, L and m are as defined for Formula I, R₁₁is hydrogen, C1-C3 alkyl or hydroxyalkyl, and the piperidinyl ring isoptionally substituted with R⁸ wherein R⁸ is as defined for Formula I.

Also included are compounds of Formula I having the Formula I-B:

where R¹, R³, R⁴, R⁹, L and m are as defined for Formula I, R² isheterocyclylalkyl optionally substituted with one or more R⁹, and thepiperidinyl ring is optionally substituted with R⁸, where R⁸ is asdefined for Formula I.

In another aspect of the invention, pharmaceutical compositions areprovided comprising a therapeutically effective amount of a compound ofthe present invention or a pharmaceutically acceptable salt thereof anda pharmaceutically acceptable excipient.

In yet another aspect of the invention, methods for inhibiting KRas G12Cactivity in a in a cell, comprising contacting the cell with a compoundof Formula I, Formula I-A or Formula 1-B. In one embodiment, thecontacting is in vitro. In one embodiment, the contacting is in vivo.

Also provided herein is a method of inhibiting cell proliferation, invitro or in vivo, the method comprising contacting a cell with aneffective amount of a compound of Formula I, Formula I-A or Formula 1-B,or a pharmaceutically acceptable salt thereof, or a pharmaceuticalcomposition thereof as defined herein.

Also provided are methods for treating cancer in a patient comprisingadministering a therapeutically effective amount of a compound orpharmaceutical composition of the present invention or apharmaceutically acceptable salt thereof to a patient in need thereof.

Also provided herein is a method of treating a KRas G12C-associateddisease or disorder in a patient in need of such treatment, the methodcomprising administering to the patient a therapeutically effectiveamount of a compound of Formula I, Formula I-A or Formula 1-B, or apharmaceutically acceptable salt or solvate thereof, or a pharmaceuticalcomposition thereof as defined herein.

Also provided herein is a compound of Formula I, Formula I-A or Formula1-B, or a pharmaceutically acceptable salt or solvate thereof, or apharmaceutical composition thereof as defined herein for use in therapy.

Also provided herein is a compound of Formula I, Formula I-A or Formula1-B, or a pharmaceutically acceptable salt or solvate thereof or apharmaceutical composition thereof as defined herein for use in thetreatment of cancer.

Also provided herein is a compound of Formula I, Formula I-A or Formula1-B, or a pharmaceutically acceptable salt or solvate thereof for use inthe inhibition of KRas G12C.

Also provided herein is a compound of Formula I, Formula I-A or Formula1-B, or a pharmaceutically acceptable salt or solvate thereof or apharmaceutical composition thereof as defined herein, for use in thetreatment of a KRas G12C-associated disease or disorder.

Also provided herein is the use of a compound of Formula I, Formula I-Aor Formula 1-B or a pharmaceutically acceptable salt or solvate thereof,as defined herein in the manufacture of a medicament for the treatmentof cancer.

Also provided herein is a use of a compound of Formula I, Formula I-A orFormula 1-B, or a pharmaceutically acceptable salt or solvate thereof,as defined herein in the manufacture of a medicament for the inhibitionof activity of KRas G12C.

Also provided herein is the use of a compound of Formula I, Formula I-Aor Formula 1-B, or a pharmaceutically acceptable salt or solvatethereof, as defined herein, in the manufacture of a medicament for thetreatment of a KRas G12C-associated disease or disorder.

Also provided herein is a method for treating cancer in a patient inneed thereof, the method comprising (a) determining that the cancer isassociated with a KRas G12C mutation (e.g., a KRas G12C-associatedcancer); and (b) administering to the patient a therapeuticallyeffective amount of a compound of Formula I, Formula I-A or Formula 1-Bor a pharmaceutically acceptable salt thereof, or a pharmaceuticalcomposition thereof.

Also provided herein is a process for preparing a compound of Formula I,Formula I-A or Formula 1-B, or a pharmaceutically acceptable salt orsolvate thereof.

Also provided herein is a compound of Formula I, Formula I-A or Formula1-B, or a pharmaceutically acceptable salt thereof obtained by a processof preparing the compound as defined herein.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to inhibitors of KRas G12C. In particular,the present invention relates to compounds that irreversibly inhibit theactivity of KRas G12C, pharmaceutical compositions comprising atherapeutically effective amount of the compounds and methods of usetherefor.

Definitions

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as is commonly understood by one of skill in theart to which this invention belongs. All patents, patent applications,and publications referred to herein are incorporated by reference.

As used herein, “KRas G12C” refers to a mutant form of a mammalian KRasprotein that contains an amino acid substitution of a cysteine for aglycine at amino acid position 12. The assignment of amino acid codonand residue positions for human KRas is based on the amino acid sequenceidentified by UniProtKB/Swiss-Prot P01116: Variant p.Gly12Cys.

As used herein, a “KRas G12C inhibitor” refers to compounds of thepresent invention that are represented by formulae (I) as describedherein. These compounds are capable of negatively modulating orinhibiting all or a portion of the enzymatic activity of KRas G12C. TheKRas G12C inhibitors of the present invention interact with andirreversibly bind to KRas G12C by forming a covalent adduct with thesulfhydryl side chain of the cysteine residue at position 12 resultingin the inhibition of the enzymatic activity of KRas G12C.

A “KRas G12C-associated disease or disorder” as used herein refers todiseases or disorders associated with or mediated by or having a KRasG12C mutation. A non-limiting example of a KRas G12C-associated diseaseor disorder is a KRas G12C-associated cancer.

As used herein, the term “subject,” “individual,” or “patient,” usedinterchangeably, refers to any animal, including mammals such as mice,rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses,primates, and humans. In some embodiments, the patient is a human. Insome embodiments, the subject has experienced and/or exhibited at leastone symptom of the disease or disorder to be treated and/or prevented.In some embodiments, the subject has been identified or diagnosed ashaving a cancer having a KRas G12C mutation (e.g., as determined using aregulatory agency-approved, e.g., FDA-approved, assay or kit). In someembodiments, the subject has a tumor that is positive for a KRas G12Cmutation (e.g., as determined using a regulatory agency-approved assayor kit). The subject can be a subject with a tumor(s) that is positivefor a KRas G12C mutation (e.g., identified as positive using aregulatory agency-approved, e.g., FDA-approved, assay or kit). Thesubject can be a subject whose tumors have a KRas G12C mutation (e.g.,where the tumor is identified as such using a regulatoryagency-approved, e.g., FDA-approved, kit or assay). In some embodiments,the subject is suspected of having a KRas G12C gene-associated cancer.In some embodiments, the subject has a clinical record indicating thatthe subject has a tumor that has a KRas G12C mutation (and optionallythe clinical record indicates that the subject should be treated withany of the compositions provided herein).

In some embodiments of any of the methods or uses described herein, anassay is used to determine whether the patient has KRas G12C mutationusing a sample (e.g., a biological sample or a biopsy sample (e.g., aparaffin-embedded biopsy sample) from a patient (e.g., a patientsuspected of having a KRas G12C-associated cancer, a patient having oneor more symptoms of a KRas G12C-associated cancer, and/or a patient thathas an increased risk of developing a KRas G12C-associated cancer) caninclude, for example, next generation sequencing, immunohistochemistry,fluorescence microscopy, break apart FISH analysis, Southern blotting,Western blotting, FACS analysis, Northern blotting, and PCR-basedamplification (e.g., RT-PCR and quantitative real-time RT-PCR). As iswell-known in the art, the assays are typically performed, e.g., with atleast one labelled nucleic acid probe or at least one labelled antibodyor antigen-binding fragment thereof.

The term “regulatory agency” is a country's agency for the approval ofthe medical use of pharmaceutical agents with the country. For example,a non-limiting example of a regulatory agency is the U.S. Food and DrugAdministration (FDA).

The term “amino” refers to —NH₂;

The term “acyl” refers to —C(O)CH₃.

The term “alkyl” as employed herein refers to straight and branchedchain aliphatic groups having from 1 to 12 carbon atoms, 1-8 carbonatoms 1-6 carbon atoms, or 1-3 carbon atoms which is optionallysubstituted with one, two or three substituents. Examples of alkylgroups include, without limitation, methyl, ethyl, propyl, isopropyl,butyl, isobutyl, sec-butyl, tert-butyl, pentyl, and hexyl.

The term “haloalkyl” refers to an alkyl chain in which one or morehydrogen has been replaced by a halogen. Examples of haloalkyls aretrifluoromethyl, difluoromethyl and fluoromethyl.

The term “haloalkyloxy” refers to —O-haloalkyl.

An “alkylene,” group is an alkyl group, as defined hereinabove, that ispositioned between and serves to connect two other chemical groups.Exemplary alkylene groups include, without limitation, methylene,ethylene, propylene, and butylene.

The term “alkoxy” refers to —OC1-C6 alkyl.

The term “cycloalkyl” as employed herein includes saturated andpartially unsaturated cyclic hydrocarbon groups having 3 to 12 carbons,for example 3 to 8 carbons, and as a further example 3 to 6 carbons,wherein the cycloalkyl group additionally is optionally substituted.Examples of cycloalkyl groups include, without limitation, cyclopropyl,cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl,cycloheptyl, and cyclooctyl.

The term “heteroalkyl” refers to an alkyl group, as defined hereinabove,wherein one or more carbon atoms in the chain are replaced by aheteroatom selected from the group consisting of O, S, and N.

As used herein, the term “hydroxyalkyl” refers to -alkyl-OH.

The term “dihydroxyalkyl” refers to an alkyl group as defined hereinwherein two carbon atoms are each substituted with a hydroxyl group.

The term “alkylaminyl” refers to —NR^(x)-alkyl, wherein R^(x) ishydrogen. In one embodiment, R^(x) is hydrogen.

The term “dialkylaminyl” refers to —N(R^(y))₂, wherein each R is C1-C3alkyl.

The term “alkylaminylalkyl” refers to -alkyl-NR^(x)-alkyl, wherein R^(x)is hydrogen. In one embodiment, R^(x) is hydrogen.

The term “dialkylaminylalkyl” refers to -alkyl-N(R^(y))₂, wherein each Ris C1-C4 alkyl, wherein the alkyl of the -alkyl-N(R^(y))₂ may beoptionally substituted with hydroxy or hydroxyalkyl.

An “aryl” group is a C₆-C₁₄ aromatic moiety comprising one to threearomatic rings, which is optionally substituted. As one embodiment, thearyl group is a C₆-C₁₀ aryl group. Examples of aryl groups include,without limitation, phenyl, naphthyl, anthracenyl, and fluorenyl.

An “aralkyl” or “arylalkyl” group comprises an aryl group covalentlylinked to an alkyl group, either of which may independently beoptionally substituted or unsubstituted. An example of an aralkyl groupis (C₁-C₆)alkyl(C₆-C₁₀)aryl, including, without limitation, benzyl,phenethyl, and naphthylmethyl. An example of a substituted aralkyl iswherein the alkyl group is substituted with hydroxyalkyl.

A “heterocyclyl” or “heterocyclic” group is a ring structure having fromabout 3 to about 12 atoms, for example 4 to 8 atoms, wherein one or moreatoms are selected from the group consisting of N, O, and S, theremainder of the ring atoms being carbon. The heterocyclyl may be amonocyclic, a bicyclic, a spirocyclic or a bridged ring system. Theheterocyclic group is optionally substituted with R⁷ on carbon ornitrogen at one or more positions, wherein R⁷ is as defined for FormulaI. The heterocyclic group is also independently optionally substitutedon nitrogen with alkyl, aryl, aralkyl, alkylcarbonyl, alkylsulfonyl,arylcarbonyl, arylsulfonyl, alkoxycarbonyl, aralkoxycarbonyl, or onsulfur with oxo or lower alkyl. Examples of heterocyclic groups include,without limitation, epoxy, azetidinyl, aziridinyl, tetrahydrofuranyl,tetrahydropyranyl, pyrrolidinyl, pyrrolidinonyl, piperidinyl,piperazinyl, imidazolidinyl, thiazolidinyl, dithianyl, trithianyl,dioxolanyl, oxazolidinyl, oxazolidinonyl, decahydroquinolinyl,piperidonyl, 4-piperidinonyl, thiomorpholinyl, thiomorpholinyl 1,1dioxide, morpholinyl, oxazepanyl, azabicyclohexanes, azabicycloheptanesand oxa azabiocycloheptanes. Specifically excluded from the scope ofthis term are compounds having adjacent annular O and/or S atoms.

The term “heterocyclylalkyl” refers to a heterocyclyl group as definedherein linked to the remaining portion of the molecule via an alkyllinker, wherein the alkyl linker of the heterocyclylalkyl may beoptionally substituted with hydroxy or hydroxyalkyl.

As used herein, the term “heteroaryl” refers to groups having 5 to 14ring atoms, preferably 5, 6, 9, or 10 ring atoms; having 6, 10, or 14πelectrons shared in a cyclic array; and having, in addition to carbonatoms, from one to three heteroatoms per ring selected from the groupconsisting of N, O, and S. Examples of heteroaryl groups includeacridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl,benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl,benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl,carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl,cinnolinyl, furanyl, furazanyl, imidazolinyl, imidazolyl, 1H-indazolyl,indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl,isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl,isothiazolyl, isoxazolyl, methylenedioxyphenyl, naphthyridinyl,octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl,1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl,oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl,phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl,piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl,pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole,pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolinyl,2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl,quinoxalinyl, quinuclidinyl, tetrahydroisoquinolinyl,tetrahydroquinolinyl, tetrazolyl, 6H-1,2,5-thiadiazinyl,1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl,1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl,thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl,1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, andxanthenyl.

A “heteroarylalkyl” group comprises a heteroaryl group covalently linkedto an alkyl group, wherein the radical is on the alkyl group, either ofwhich is independently optionally substituted or unsubstituted. Examplesof heteroarylalkyl groups include a heteroaryl group having 5, 6, 9, or10 ring atoms bonded to a C1-C6 alkyl group. Examples of heteroaralkylgroups include pyridylmethyl, pyridylethyl, pyrrolylmethyl,pyrrolylethyl, imidazolylmethyl, imidazolylethyl, thiazolylmethyl,thiazolylethyl, benzimidazolylmethyl, benzimidazolylethylquinazolinylmethyl, quinolinylmethyl, quinolinylethyl,benzofuranylmethyl, indolinylethyl isoquinolinylmethyl, isoinodylmethyl,cinnolinylmethyl, and benzothiophenylethyl. Specifically excluded fromthe scope of this term are compounds having adjacent annular O and/or Satoms.

As used herein, “an effective amount” of a compound is an amount that issufficient to negatively modulate or inhibit the activity of KRas G12C.Such amount may be administered as a single dosage or may beadministered according to a regimen, whereby it is effective.

As used herein, a “therapeutically effective amount” of a compound is anamount that is sufficient to ameliorate, or in some manner reduce asymptom or stop or reverse progression of a condition, or negativelymodulate or inhibit the activity of KRas G12C. Such amount may beadministered as a single dosage or may be administered according to aregimen, whereby it is effective.

As used herein, treatment means any manner in which the symptoms orpathology of a condition, disorder or disease are ameliorated orotherwise beneficially altered. Treatment also encompasses anypharmaceutical use of the compositions herein.

As used herein, amelioration of the symptoms of a particular disorder byadministration of a particular pharmaceutical composition refers to anylessening, whether permanent or temporary, lasting or transient that canbe attributed to or associated with administration of the composition.

Compounds

In one aspect of the invention, compounds are provided represented byformula (I):

or a pharmaceutically acceptable salt thereof, wherein:

X is a 4-12 membered saturated or partially saturated monocyclic,bridged or spirocyclic ring, wherein the saturated or partiallysaturated monocyclic ring is optionally substituted with one or more R⁸;

Y is a bond, O, S or NR⁵;

R¹ is —C(O)C(R^(A))

C(R^(B))_(p) or —SO₂C(R^(A))

C(R^(B))_(p);

R² is hydrogen, alkyl, hydroxyalkyl, dihydroxyalkyl, alkylaminylalkyl,dialkylaminylalkyl, —Z—NR⁵R¹⁰, heterocyclyl, heterocyclylalkyl, aryl,heteroaryl, or heteroarylalkyl, wherein each of the Z, heterocyclyl,heterocyclylalkyl, aryl, heteroaryl, and heteroarylalkyl may beoptionally substituted with one or more R⁹;

Z is C1-C4 alkylene;

each R³ is independently C1-C3 alkyl, oxo, or haloalkyl;

L is a bond, —C(O)—, or C1-C3 alkylene;

R⁴ is hydrogen, cycloalkyl, heterocyclyl, aryl, aralkyl or heteroaryl,wherein each of the cycloalkyl, heterocyclyl, aryl, aralkyl andheteroaryl may be optionally substituted with one or more R⁶ or R⁷;

each R⁵ is independently hydrogen or C1-C3 alkyl;

R⁶ is cycloalkyl, heterocyclyl, heterocyclylalkyl, aryl, or heteroaryl,wherein each of the cycloalkyl, heterocyclyl, aryl, or heteroaryl may beoptionally substituted with one or more R⁷;

each R⁷ is independently halogen, hydroxyl, C1-C6 alkyl, cycloalkyl,alkoxy, haloalkyl, amino, cyano, heteroalkyl, hydroxyalkyl orQ-haloalkyl, wherein Q is O or S;

R⁸ is oxo, C1-C3 alkyl, C2-C4 alkynyl, heteroalkyl, cyano, —C(O)OR⁵,—C(O)N(R⁵)₂, —N(R⁵)₂, wherein the C1-C3 alkyl may be optionallysubstituted with cyano, halogen, —OR⁵, —N(R⁵)₂, or heteroaryl;

each R⁹ is independently hydrogen, oxo, acyl, hydroxyl, hydroxyalkyl,cyano, halogen, C1-C6 alkyl, aralkyl, haloalkyl, heteroalkyl,cycloalkyl, heterocyclylalkyl, alkoxy, dialkylaminyl, dialkylamidoalkyl,or dialkylaminylalkyl, wherein the C1-C6 alkyl may be optionallysubstituted with cycloalkyl;

each R¹⁰ is independently hydrogen, acyl, C1-C3 alkyl, heteroalkyl orhydroxyalkyl;

R^(A) is absent, hydrogen, or C1-C3 alkyl;

each R^(B) is independently hydrogen, C1-C3 alkyl, alkylaminylalkyl,dialkylaminylalkyl or heterocyclylalkyl;

m is zero or an integer between 1 and 2;

p is one or two; and wherein,

when

is a triple bond then R^(A) is absent, R^(B) is present and p equalsone;

or when

is a double bond then R^(A) is present, R^(B) is present and p equalstwo, or R^(A), R^(B) and the carbon atoms to which they are attachedform a 5-8 membered partially saturated cycloalkyl optionallysubstituted with one or more R⁷.

In certain embodiments, R¹—X is:

wherein R¹ is are defined for Formula I and the piperazinyl ring isoptionally substituted with R⁸, where R⁸ is as defined for Formula I. Incertain embodiments, R⁸ is C1-C3 alkyl wherein the alkyl is optionallysubstituted with cyano or OR⁵, or —C(O)N(R⁵)₂, wherein each R⁵ isindependently hydrogen or C1-C3 alkyl.

In particular embodiments, R¹ is —C(O)C(R^(A))

C(R^(B))_(p) where R^(A), R^(B) and p are as defined for Formula I. Inone embodiment, R¹ is —C(O)C(R^(A))

C(R^(B))_(p), wherein is a triple bond and R^(A) is absent, p is one andR^(B) is C1-C3 alkyl. In one embodiment, R¹ is —C(O)C(R^(A))

C(R^(B))_(p), wherein

is a double bond and R^(A) is hydrogen or C1-C3alkyl, p is two and eachR^(B) is independently hydrogen, C1-C3alkyl, dialkylaminylalkyl orheterocyclylalkyl. In one embodiment, R¹ is —C(O)C(R^(A))═C(R^(B))_(p),wherein R^(A) is hydrogen or C1-C3alkyl, p is two, one of said R^(B) ishydrogen, C1-C3alkyl, dialkylaminylalkyl or heterocyclylalkyl and theother R^(B) is hydrogen or C1-C3alkyl. In one embodiment, R¹ is—C(O)CH═CH₂.

In one embodiment, Y is O or NR¹ and R² is selected from the groupconsisting of alkyl, hydroxyalkyl, dihydroxyalkyl, alkylaminylalkyl,dialkylaminylalkyl, heterocyclyl, heterocyclylalkyl, and heteroaryl. Inone embodiment, Y is O and R² is hydroxyalkyl, dihydroxyalkyl,alkylaminylalkyl, or dialkylaminylalkyl, wherein the alkylaminylalkyl ordialkylaminylalkyl is optionally substituted with one or more R⁹. In oneembodiment, the optionally substituted alkylaminylalkyl ordialkylaminylalkyl is independently selected frommethylaminylpropan-2-yl, dimethylaminylethyl, methylethylaminylethyl,dimethylaminylpropanyl, dimethylaminylpropan-2-yl,dimethylaminylbutanyl, dimethylaminylbutan-2-yl,2-dimethylaminylpropanol, or diethylaminylethyl. In one embodiment, Y isO or NR⁵ and R² is heterocyclyl or heterocyclylalkyl optionallysubstituted with one or more R⁹. Nonlimiting examples of one or more R⁹when R² is heterocyclyl or heterocyclylalkyl include C1-C3 alkyl, acyl,oxo, cyano, alkoxy, cycloalkyl, cycloalkylmethyl, halogen, and hydroxyl.Nonlimiting examples of R² heterocyclyls optionally substituted with oneor more R⁹ include azetidinyl, C1-C3alkyl-substituted azetidinyl (e.g.,methylazetidinyl), halo-substituted azetidinyl (e.g.,difluoroazetidinyl), tetrahydropyran, pyrrolidinyl, C1-C3alkyl-substituted pyrrolidinyl (e.g., methylpyrrolidinyl,dimethylpyrrolidinyl, and isopropylpyrrolidinyl),cycloalkylalkylpyrrolidinyl, hydroxypyrrolindinyl, halo-substitutedpyrrolidinyl (e.g., fluoropyrrolidinyl and difluoropyrrolidinyl),methoxyethylpyrrolidinyl, (N-methyl)methoxypyrrolidinyl, piperazinyl,dimethylaminylpyrrolidinyl, morpholinyl, methylmorpholinyl,1,4-oxazepanyl, piperdinyl, C1-C3 alkyl-substituted piperidinyl (e.g.,methylpiperidinyl), acylpiperdinyl, cyanopiperdinyl,cycloalkylpiperdinyl, halopiperdinyl (e.g., fluoropiperdinyl),dihalopiperdinyl (e.g., difluoropiperdinyl), alkoxypiperdinyl,pyrrolidonyl, piperidonyl, thiomorpholinyl-1,1-dioxide,3-azabicyclo[3.1.0]hexanyl, oxa-5-azabicyclo[2.2.1]heptan-5-yl, andazabicyclo[2.2.1]heptan-2-yl.

In one embodiment, Y is O and R² is heteroarylalkyl optionallysubstituted with one or more R⁹. In one embodiment, the heteroarylportion of the heteroarylalkyl is pyridinyl.

In one embodiment, Y is O and R² is —ZR⁵R¹⁰. In one embodiment, R⁵ isC1-C3 alkyl and R¹⁰ is independently selected from acyl, hydroxyalkyl oralkoxy.

In one embodiment, Y is a bond and R² is hydrogen, heterocyclyl or aryl,wherein said heterocyclyl and aryl are optionally substituted with oneor more R⁹.

In one embodiment, Y is a bond and R² is hydrogen.

In one embodiment, Y is a bond and R² is heterocyclyl optionallysubstituted with one or more R⁹. In one embodiment, Y is a bond and R²is heterocyclyl optionally substituted with methyl, halogen ordimethylamino. Nonlimiting examples of R² heterocyclyls includeazetidinyl, piperidinyl, piperazinyl, morpholinyl, and pyrrolidinyl.

In one embodiment, Y is a bond and R² is aryl optionally substitutedwith one or more R⁹. In one embodiment, the aryl is phenyl substitutedwith heterocyclylalkyl.

In certain other embodiments when X is a monocyclic ring, R⁴ is aryl. Inone embodiment, R⁴ is selected from the group consisting of phenyl andnaphthyl and is optionally substituted with one or more R⁶ or R⁷.Examples of R⁷ substituents include halogen, hydroxyl, C1-C6 alkyl(e.g., C1-C3 alkyl), cycloalkyl, haloalkyl, Q-haloalkyl, amino, cyano,hydroxyalkyl and alkoxy. In one embodiment, the aryl is phenylsubstituted with one or more R⁷ groups independently selected fromhalogen, hydroxyl, C1-C3 alkyl, haloalkyl, Q-haloalkyl, and alkoxy. Inone embodiment, the aryl is phenyl substituted with one or more R⁷groups independently selected from halogen, haloalkyl, methyl,isopropyl, methoxy, Q-haloalkyl and hydroxyl. In one embodiment, thearyl is phenyl substituted with one or more R⁷ groups independentlyselected from methyl, trifluoromethyl, 2,2,2-trifluoroethyl, hydroxyl,trifluoromethoxy, hydroxyl, fluoro, chloro, isopropyl, cyclopropyl andtrifluoromethylthio. In one embodiment, the aryl is phenyl substitutedwith one to three R⁷ groups independently selected from hydroxyl,fluorine and chlorine. In one embodiment, the aryl is phenyl substitutedwith hydroxyl and C1-C3 alkyl or two C1-C3 alkyl. In one embodiment, thearyl is phenyl substituted with Q-haloalkyl and hydroxyl or fluorine.

In one embodiment, R⁴ is aryl wherein aryl is naphthyl optionallysubstituted with one or more R⁷. In one embodiment, the aryl is naphthylsubstituted with one or more R⁷ groups independently selected fromhalogen, hydroxyl, C1-C3 alkyl, haloalkyl, Q-haloalkyl, and alkoxy. Inone embodiment, the aryl is naphthyl substituted with one or more R⁷groups independently selected from halogen, haloalkyl, methyl,isopropyl, methoxy, Q-haloalkyl and hydroxyl. In one embodiment, R⁴ isnaphthyl optionally substituted with one or more R⁷ substituentsindependently selected from hydroxyl, halogen, C1-C3 alkyl, amino, andhaloalkyl. In one embodiment, R⁴ is naphthyl optionally substituted withone to three R⁷ substituents independently selected from difluoromethyl,methyl, hydroxyl, amino, fluoro, and chloro.

In one embodiment, the aryl is naphthyl optionally substituted with oneor more halogen. In one embodiment, the aryl is naphthyl substitutedwith hydroxyl and trifluoromethyl or C1-C3alkyl. In one embodiment, thearyl is naphthyl substituted with hydroxyl.

In one embodiment, R⁴ is heteroaryl optionally substituted with one ormore R⁷. In one embodiment, R⁴ is heteroaryl optionally substituted withone or more R⁷ independently selected from halogen, hydroxyl, C1-C3alkyl, haloalkyl, Q-haloalkyl, alkoxy and amino. In one embodiments, R⁴is indoyl, indazolyl, quinolinyl, isoquinolinyl, pyridinyl orbenzo[d]thiazolyl optionally substituted with one or more R⁷. In oneembodiments, R⁴ is indoyl, indazolyl, quinolinyl, isoquinolinyl,pyridinyl or benzo[d]thiazolyl optionally substituted with one or moreR⁷ independently selected from halogen, hydroxyl, C1-C3 alkyl,haloalkyl, Q-haloalkyl, alkoxy and amino.

In yet other embodiments, R⁴ is heteroaryl, optionally an indoyl or anindazolyl, each of which may be substituted with one or more R⁷. In oneembodiment, R⁴ is heteroaryl optionally substituted with one or more R⁷substituents independently selected from the group consisting ofhalogen, hydroxyl, C1-C3 alkyl, haloalkyl, Q-haloalkyl and alkoxy. Inone embodiment, the R⁴ heteroaryl is indazolyl optionally substitutedwith one or two R⁷ independently selected from alkoxy, haloalkyl, andC1-C6 alkyl. In other embodiments, the R⁴ heteroaryl is a quinolinyl orisoquinolinyl, each optionally substituted with one or more R⁷. In oneembodiment, the R⁴ heteroaryl is a quinolinyl or isoquinolinyl, eachoptionally substituted with one or more R⁷ independently selected fromamino, hydroxyl, C1-C3 alkyl, and hydroxyl. In one embodiment, the R⁴heteroaryl is a quinolinyl or isoquinolinyl, each optionally substitutedwith R⁷ selected from hydroxyl and amino. In one embodiment, the R⁴heteroaryl is a pyridinyl optionally substituted with one or more R⁷. Inone embodiment, the R⁴ heteroaryl is pyridinyl optionally substitutedwith one or more R⁷ independently selected from C1-C3 alkyl, halogen andhaloalkyl. In other embodiments, the R⁴ heteroaryl is benzo[d]thiazolyloptionally substituted with one or more R⁷, such as hydroxyl, one or twoC1-C3 alkyl, or hydroxyl and one or two C1-C3 alkyl. In one embodiment,the R⁴ heteroaryl is indolyl optionally substituted with one or more R⁷.In one embodiment, the R⁴ heteroaryl is indolyl optionally substitutedwith one or two R⁷ independently selected from hydroxyl and C1-C3alkyl.

In one embodiment, where X is a monocyclic ring, R⁴ is aralkyl. Incertain embodiments, the aralkyl is benzyl. In other embodiments, thealkyl of the benzyl group is optionally substituted with hydroxyalkyl.

In one embodiment, L is a bond.

In one embodiment, m is one and R³ is C1-C3 alkyl.

In one embodiment, m is one and R³ is oxo.

In one embodiment, R⁸ is heteroalkyl, C2-C4 alkynyl or C1-C3 alkyloptionally substituted with —OR⁵, cyano or heteroaryl. In oneembodiment, R⁸ is methyl, cyanomethyl, methoxymethyl, hydroxymethyl. Inone embodiment, R⁸ is methyl. In one embodiment, R⁸ is cyanomethyl. Inone embodiment, R⁸ is hydroxymethyl.

In one embodiment, Formula I includes compounds having the Formula I-A:

wherein R¹, R³, R⁴, R⁵, R¹⁰, L and m are as defined for Formula I, R¹¹is hydrogen, methyl or hydroxyalkyl, and the piperidinyl ring isoptionally substituted with R⁸ wherein R⁸ is as defined for Formula I.In one embodiment, L is a bond. In one embodiment, R⁴ is aryl orheteroaryl, each of which is optionally substituted with one or more R⁶or R⁷. In one embodiment, R⁴ is aryl or heteroaryl, each of which isoptionally substituted with one or more R⁷. In one embodiment, each R⁷is independently selected from hydroxyl, amino, halogen, C1-C3 alkyl,haloalkyl, Q-haloalkyl, cycloalkyl and alkoxy. In one embodiment, R⁵ andR¹⁰ are each C1-C3 alkyl. In one embodiment, the aryl is phenylsubstituted with one or more R⁷ groups independently selected fromhalogen, hydroxyl, C1-C3 alkyl, haloalkyl, Q-haloalkyl, and alkoxy. Inone embodiment, the aryl is phenyl substituted with one or more R⁷groups independently selected from halogen, haloalkyl, methyl,isopropyl, methoxy, Q-haloalkyl and hydroxyl. In one embodiment, thearyl is phenyl substituted with one or more R⁷ groups independentlyselected from methyl, trifluoromethyl, 2,2,2-trifluoroethyl, hydroxyl,trifluoromethoxy, hydroxyl, fluoro, chloro, isopropyl, cyclopropyl andtrifluoromethylthio. In one embodiment, the aryl is phenyl substitutedwith one to three R⁷ groups independently selected from hydroxyl,fluorine and chlorine. In one embodiment, the aryl is phenyl substitutedwith hydroxyl and C1-C3 alkyl or two C1-C3 alkyl. In one embodiment, thearyl is phenyl substituted with Q-haloalkyl and hydroxyl or fluorine. Inone embodiment, the aryl is naphthyl substituted with one or more R⁷groups independently selected from halogen, hydroxyl, C1-C3 alkyl,haloalkyl, Q-haloalkyl, and alkoxy. In one embodiment, the aryl isnaphthyl substituted with one or more R⁷ groups independently selectedfrom halogen, haloalkyl, methyl, isopropyl, methoxy, Q-haloalkyl andhydroxyl. In one embodiment, R⁴ is naphthyl optionally substituted withone or more R⁷ substituents independently selected from hydroxyl,halogen, C1-C3 alkyl, amino, and haloalkyl. In one embodiment, R⁴ isnaphthyl optionally substituted with one to three R⁷ substituentsindependently selected from difluoromethyl, methyl, hydroxyl, amino,fluoro, and chloro. In one embodiment, the aryl is naphthyl optionallysubstituted with one or more halogen. In one embodiment, the aryl isnaphthyl substituted with hydroxyl and trifluoromethyl or C1-C3alkyl. Inone embodiment, the aryl is naphthyl substituted with hydroxyl. In oneembodiment, R⁴ is heteroaryl, wherein the heteroaryl is indazolyloptionally substituted with one or two R⁷ independently selected fromalkoxy, haloalkyl, and C1-C6 alkyl. In one embodiment, R⁴ is heteroaryl,wherein the heteroaryl is quinolinyl or isoquinolinyl, each optionallysubstituted with one or more R⁷. In one embodiment, R⁴ is heteroaryl,wherein the heteroaryl is quinolinyl or isoquinolinyl, each optionallysubstituted with one or more R⁷ independently selected from amino,hydroxyl, C1-C3alkyl, and hydroxyl. In one embodiment, the R⁴ heteroarylis a pyridinyl optionally substituted with one or more R⁷. In oneembodiment, the R⁴ heteroaryl is pyridinyl optionally substituted withone or more R⁷ independently selected from C1-C3 alkyl, halogen andhaloalkyl. In one embodiment, the R⁴ heteroaryl is benzo[d]thiazolyloptionally substituted with one or more R⁷, such as hydroxyl, one or twoC1-C3 alkyl, or hydroxyl and one or two C1-C3 alkyl. In one embodiment,the R⁴ heteroaryl is indolyl optionally substituted with one or more R⁷.In one embodiment, the R⁴ heteroaryl is indolyl optionally substitutedwith one or two R⁷ independently selected from hydroxyl and C1-C3alkyl.In one embodiment, R¹¹ is methyl. In one embodiment, the piperidinylring is unsubstituted. In one embodiment, the piperidinyl ring issubstituted with R⁸. In one embodiment, R⁸ is C1-C3 alkyl optionallysubstituted with cyano or hydroxyl. In one embodiment, R⁸ is methyl,cyanomethyl or hydroxymethyl. In one embodiment, R⁸ is methyl. In oneembodiment, R⁸ is cyanomethyl. In one embodiment, R⁸ is hydroxymethyl.In another embodiment, R⁵ and R¹⁰ are each C1-C3 alkyl, R¹¹ is methyl,R⁸ is methyl, cyanomethyl or hydroxymethyl, L is a bond, and R⁴ is arylor heteroaryl, each optionally substituted with one or more R⁶ or R⁷.

In one embodiment, Formula I includes compounds having the Formula I-B:

and R¹, R³, R⁴, R⁹, L and m are as defined for Formula I, R² isheterocyclylalkyl optionally substituted with one or more R⁹, and thepiperidinyl ring is optionally substituted with R⁸, where R⁸ is asdefined for Formula I. In one embodiment, the heterocyclyl portion ofthe R² heterocyclylalkyl is a monocyclic, bicyclic, or bridged ringsystem having one or two ring heteroatoms independently selected from Nand O. In one embodiment, R² heterocyclyl is pyrrolidinyl, piperidinyl,piperazinyl, morpholinyl, 1,4-oxazepanyl, thiomorpholinyl-1,1-dioxide,3-azabicyclo[3.1.0]hexanyl, 2-oxa-5-azabicyclo[2.2.1]heptan-5-yl, andazabicyclo[2.2.1]heptan-2-yl, optionally substituted with one or moreR⁹. In one embodiment, each R⁹ is selected from acyl, oxo, halogen,cyano, C1-C3 alkyl, alkoxy, hydroxyalkyl, heteroalkyl, cycloalkyl,aralkyl and dialkylamidoalkyl. In one embodiment, Lisa bond. In oneembodiment, R⁴ is aryl or heteroaryl, each of which is optionallysubstituted with one or more R⁶ or R⁷. In one embodiment, R⁴ is aryl orheteroaryl, each of which is optionally substituted with one or more R⁷.In one embodiment, each R⁷ is independently selected from hydroxyl,amino, halogen, C1-C3 alkyl, haloalkyl, Q-haloalkyl, cycloalkyl andalkoxy. In one embodiment, the aryl is phenyl substituted with one ormore R⁷ groups independently selected from halogen, hydroxyl, C1-C3alkyl, haloalkyl, Q-haloalkyl, and alkoxy. In one embodiment, the arylis phenyl substituted with one or more R⁷ groups independently selectedfrom halogen, haloalkyl, methyl, isopropyl, methoxy, Q-haloalkyl andhydroxyl. In one embodiment, the aryl is phenyl substituted with one ormore R⁷ groups independently selected from methyl, trifluoromethyl,2,2,2-trifluoroethyl, hydroxyl, trifluoromethoxy, hydroxyl, fluoro,chloro, isopropyl, cyclopropyl and trifluoromethylthio. In oneembodiment, the aryl is phenyl substituted with one to three R⁷ groupsindependently selected from hydroxyl, fluorine and chlorine. In oneembodiment, the aryl is phenyl substituted with hydroxyl and C1-C3 alkylor two C1-C3 alkyl. In one embodiment, the aryl is phenyl substitutedwith Q-haloalkyl and hydroxyl or fluorine. In one embodiment, the arylis naphthyl substituted with one or more R⁷ groups independentlyselected from halogen, hydroxyl, C1-C3 alkyl, haloalkyl, Q-haloalkyl,and alkoxy. In one embodiment, the aryl is naphthyl substituted with oneor more R⁷ groups independently selected from halogen, haloalkyl,methyl, isopropyl, methoxy, Q-haloalkyl and hydroxyl. In one embodiment,R⁴ is naphthyl optionally substituted with one or more R⁷ substituentsindependently selected from hydroxyl, halogen, C1-C3 alkyl, amino, andhaloalkyl. In one embodiment, R⁴ is naphthyl optionally substituted withone to three R⁷ substituents independently selected from difluoromethyl,methyl, hydroxyl, amino, fluoro, and chloro. In one embodiment, the arylis naphthyl optionally substituted with one or more halogen. In oneembodiment, the aryl is naphthyl substituted with hydroxyl andtrifluoromethyl or C1-C3alkyl. In one embodiment, the aryl is naphthylsubstituted with hydroxyl. In one embodiment, R⁴ is heteroaryl, whereinthe heteroaryl is indazolyl optionally substituted with one or two R⁷independently selected from alkoxy, haloalkyl, and C1-C6 alkyl. In oneembodiment, R⁴ is heteroaryl, wherein the heteroaryl is quinolinyl orisoquinolinyl, each optionally substituted with one or more R⁷. In oneembodiment, R⁴ is heteroaryl, wherein the heteroaryl is quinolinyl orisoquinolinyl, each optionally substituted with one or more R⁷independently selected from amino, hydroxyl, C1-C3 alkyl, and hydroxyl.In one embodiment, the R⁴ heteroaryl is a pyridinyl optionallysubstituted with one or more R⁷. In one embodiment, the R⁴ heteroaryl ispyridinyl optionally substituted with one or more R⁷ independentlyselected from C1-C3 alkyl, halogen and haloalkyl. In one embodiment, theR⁴ heteroaryl is benzo[d]thiazolyl optionally substituted with one ormore R⁷, such as hydroxyl, one or two C1-C3 alkyl, or hydroxyl and oneor two C1-C3 alkyl. In one embodiment, the R⁴ heteroaryl is indolyloptionally substituted with one or more R⁷. In one embodiment, the R⁴heteroaryl is indolyl optionally substituted with one or two R⁷independently selected from hydroxyl and C1-C3 alkyl. In one embodiment,R¹¹ is methyl. In one embodiment, the piperidinyl ring is unsubstituted.In one embodiment, the piperidinyl ring is substituted with R⁸. In oneembodiment, the piperidinyl ring is unsubstituted. In one embodiment,the piperidinyl ring is substituted with R⁸. In one embodiment, R⁸ isC1-C3 alkyl optionally substituted with cyano, hydroxyl or methoxy. Inone embodiment, R⁸ is methyl, cyanomethyl, hydroxymethyl ormethoxymethyl.

In one embodiment, X is a saturated bridged ring system. Nonlimitingexamples of bridged ring systems include diazabicycloheptanes anddiazabicyclooctanes. In certain embodiments, when X is a saturatedbridged ring system, R¹ is —C(O)CH═CH₂. In one embodiment, the bridgedring system is substituted with one or two groups independently selectedfrom R⁸, where R⁸ is as defined for Formula I. In one embodiment, thebridged ring system is unsubstituted. In one embodiment, the bridgedring system is diazabicyclo[3.2.1]octan-8-yl ordiazabicyclo[3.2.1]octan-3-yl.

In one embodiment, R¹—X is:

wherein A and B are a spirocyclic ring system, wherein A and B are thesame or different and independently represent a 4-6 membered saturatedring systems, wherein the rings are optionally substituted with one ormore R⁸, wherein R⁸ is as defined for Formula I. In certain embodiments,R¹ is —C(O)CH═CH2. In certain embodiments, rings A and B areunsubstituted.

In one embodiment, the spirocyclic ring system is unsubstituted.Non-limiting examples of spirocyclic ring systems include:

In certain embodiments when A and B represent a spirocyclic ring system,R¹ is —C(O)CH═CH₂.

In one embodiment of Formula I, R² is selected from the group consistingof hydroxyalkyl, dialkylaminylalkyl, heterocyclyl and heterocyclylalkyl,wherein each of the heterocyclyl or heterocyclylalkyl are independentlyoptionally substituted with R⁹. In another embodiment, R² isheterocyclyl and heterocyclylalkyl, wherein each of the heterocyclyl orheterocyclylalkyl are independently optionally substituted with one ormore R⁹. In certain embodiments, R² is dialkylaminylalkyl optionallysubstituted with one or more R⁹. Non-limiting examples includedimethylaminylethyl, dimethylaminylpropanyl, dimethylaminylpropan-2-yl,dimethylaminylbutanyl, dimethylaminylbutan-2-yl,2-dimethylaminylpropanol, or diethylaminylethyl.

In one embodiment, Y is O and R² is selected from the group consistingof hydroxyalkyl, dialkylaminylalkyl, heterocyclyl, heterocyclylalkyl,and —ZR⁵R¹⁰, wherein R⁵ and R¹⁰ are as defined for Formula I.

In one embodiment, Y is O and R² is selected from the group consistingof hydroxyalkyl, dialkylaminylalkyl, heterocyclyl and heterocyclylalkyl,wherein each of the heterocyclyl or heterocyclylalkyl are independentlyoptionally substituted with R⁹. In another embodiment, R² isheterocyclyl and heterocyclylalkyl, wherein each of the heterocyclyl orheterocyclylalkyl are independently optionally substituted with one ormore R⁹. Non-limiting examples of R⁹ include acyl, oxo, halogen, cyano,C1-C6 alkyl, alkoxy, hydroxyalkyl, heteroalkyl, cycloalkyl, aralkyl ordialkylamidoalkyl. In certain embodiments, R² is dialkylaminylalkyloptionally substituted with one or more R⁹. Non-limiting examplesinclude dimethylaminylethyl, dimethylaminylpropanyl,dimethylaminylpropan-2-yl, dimethylaminylbutanyl,dimethylaminylbutan-2-yl, 2-dimethylaminylpropanol, ordiethylaminylethyl.

In one embodiment of Formula I, R⁴ is aryl optionally substituted withone or more R⁶ or R⁷. In one embodiment, R⁴ is phenyl or naphthyloptionally substituted with one or more R⁶ or R⁷. In one embodiment, R⁴is phenyl or naphthyl optionally substituted with one or more R⁷. In oneembodiment, R⁴ is phenyl or naphthyl optionally substituted with one ormore R⁷ substituents independently selected from halogen, hydroxyl,C1-C3alkyl, cycloalkyl, alkoxy, haloalkyl, or Q-haloalkyl wherein Q is Oor S. In one embodiment, R⁴ is phenyl or naphthyl optionally substitutedwith one or more R⁷ substituents independently selected from methyl,trifluoromethyl, hydroxyl, trifluoromethoxy, hydroxyl, fluoro, chloro,isopropyl, cyclopropyl and methylthio.

In one embodiment, R⁴ is isoquinolinyl which is optionally substitutedwith amino. In one embodiment, R⁴ is aralkyl. In certain embodiments,the aralkyl is benzyl. In one embodiment, the aralkyl is benzyl whereinthe alkyl portion is substituted with hydroxyl or hydroxyalkyl.

Nonlimiting examples of compounds of Formula (I), Formula I-A andFormula I-B are selected from the group consisting of.

and pharmaceutically acceptable salts thereof. In one embodiment, thecompounds of Formula I include trifluoroacetic acid salts of the abovecompounds. The compounds of Formula (I), Formula I-A, or Formula I-B maybe formulated into pharmaceutical compositions.

Pharmaceutical Compositions

In another aspect, the invention provides pharmaceutical compositionscomprising a KRas G12C inhibitor according to the invention and apharmaceutically acceptable carrier, excipient, or diluent. Compounds ofthe invention may be formulated by any method well known in the art andmay be prepared for administration by any route, including, withoutlimitation, parenteral, oral, sublingual, transdermal, topical,intranasal, intratracheal, or intrarectal. In certain embodiments,compounds of the invention are administered intravenously in a hospitalsetting. In one embodiment, administration may be by the oral route.

The characteristics of the carrier will depend on the route ofadministration. As used herein, the term “pharmaceutically acceptable”means a non-toxic material that is compatible with a biological systemsuch as a cell, cell culture, tissue, or organism, and that does notinterfere with the effectiveness of the biological activity of theactive ingredient(s). Thus, compositions according to the invention maycontain, in addition to the inhibitor, diluents, fillers, salts,buffers, stabilizers, solubilizers, and other materials well known inthe art. The preparation of pharmaceutically acceptable formulations isdescribed in, e.g., Remington's Pharmaceutical Sciences, 18th Edition,ed. A. Gennaro, Mack Publishing Co., Easton, Pa., 1990.

As used herein, the term pharmaceutically acceptable salt refers tosalts that retain the desired biological activity of theabove-identified compounds and exhibit minimal or no undesiredtoxicological effects. Examples of such salts include, but are notlimited to acid addition salts formed with inorganic acids (for example,hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid,nitric acid, and the like), and salts formed with organic acids such asacetic acid, oxalic acid, tartaric acid, succinic acid, malic acid,ascorbic acid, benzoic acid, tannic acid, pamoic acid, alginic acid,polyglutamic acid, naphthalenesulfonic acid, naphthalenedisulfonic acid,and polygalacturonic acid. The compounds can also be administered aspharmaceutically acceptable quaternary salts known by those skilled inthe art, which specifically include the quaternary ammonium salt of theformula —NR+Z—, wherein R is hydrogen, alkyl, or benzyl, and Z is acounterion, including chloride, bromide, iodide, —O-alkyl,toluenesulfonate, methylsulfonate, sulfonate, phosphate, or carboxylate(such as benzoate, succinate, acetate, glycolate, maleate, malate,citrate, tartrate, ascorbate, benzoate, cinnamoate, mandeloate,benzyloate, and diphenylacetate).

The active compound is included in the pharmaceutically acceptablecarrier or diluent in an amount sufficient to deliver to a patient atherapeutically effective amount without causing serious toxic effectsin the patient treated. In one embodiment, a dose of the active compoundfor all of the above-mentioned conditions is in the range from about0.01 to 300 mg/kg, for example 0.1 to 100 mg/kg per day, and as afurther example 0.5 to about 25 mg per kilogram body weight of therecipient per day. A typical topical dosage will range from 0.01-3%wt/wt in a suitable carrier. The effective dosage range of thepharmaceutically acceptable derivatives can be calculated based on theweight of the parent compound to be delivered. If the derivativeexhibits activity in itself, the effective dosage can be estimated asabove using the weight of the derivative, or by other means known tothose skilled in the art.

The pharmaceutical compositions comprising compounds of the presentinvention may be used in the methods of use described herein.

Methods of Use

In yet another aspect, the invention provides for methods for inhibitingKRas G12C activity in a cell, comprising contacting the cell in whichinhibition of KRas G12C activity is desired with an effective amount ofa compound of Formula (I), Formula I-A, or Formula I-B, pharmaceuticallyacceptable salts thereof or pharmaceutical compositions containing thecompound or pharmaceutically acceptable salt thereof. In one embodiment,the contacting is in vitro. In one embodiment, the contacting is invivo.

As used herein, the term “contacting” refers to the bringing together ofindicated moieties in an in vitro system or an in vivo system. Forexample, “contacting” a KRas G12C with a compound provided hereinincludes the administration of a compound provided herein to anindividual or patient, such as a human, having KRas G12C, as well as,for example, introducing a compound provided herein into a samplecontaining a cellular or purified preparation containing the KRas G12C.

In one embodiment, a cell in which inhibition of KRas G12C activity isdesired is contacted with an effective amount of a compound of Formula(I), Formula I-A, or Formula I-B, to negatively modulate the activity ofKRas G12C. In other embodiments, a therapeutically effective amount ofpharmaceutically acceptable salt or pharmaceutical compositionscontaining the compound of Formula (I), Formula I-A, or Formula I-B, maybe used.

By negatively modulating the activity of KRas G12C, the methodsdescribed herein are designed to inhibit undesired cellularproliferation resulting from enhanced KRas G12C activity within thecell. The cells may be contacted in a single dose or multiple doses inaccordance with a particular treatment regimen to effect the desirednegative modulation of KRas G12C. The degree of covalent modification ofKRas G12C may be monitored in vitro using well known methods, includingthose described in Example A below. In addition, the inhibitory activityof exemplary compounds in cells may be monitored, for example, bymeasuring the inhibition of KRas G12C activity of the amount ofphosphylated ERK, including those described in Example B below, toassess the effectiveness of treatment and dosages may be adjustedaccordingly by the attending medical practitioner.

In another aspect, methods of treating cancer in a patient in needthereof, comprising administering to said patient a therapeuticallyeffective amount of a compound of Formula (I), Formula I-A, or FormulaI-B, pharmaceutically acceptable salts thereof or pharmaceuticalcompositions comprising the compound or pharmaceutically acceptablesalts thereof are provided.

The compositions and methods provided herein may be used for thetreatment of a KRas G12C-associated cancer in a patient in need thereof,comprising administering to said patient a therapeutically effectiveamount of a compound of Formula (I), Formula I-A, or Formula I-B,pharmaceutically acceptable salts thereof or pharmaceutical compositionscomprising the compound or pharmaceutically acceptable salts thereof areprovided. In one embodiment, the KRas G12C-associated cancer is lungcancer.

The compositions and methods provided herein may be used for thetreatment of a wide variety of cancers including tumors such as lung,prostate, breast, brain, skin, cervical carcinomas, testicularcarcinomas, etc. More particularly, cancers that may be treated by thecompositions and methods of the invention include, but are not limitedto tumor types such as astrocytic, breast, cervical, colorectal,endometrial, esophageal, gastric, head and neck, hepatocellular,laryngeal, lung, oral, ovarian, prostate and thyroid carcinomas andsarcomas. More specifically, these compounds can be used to treat:Cardiac: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma,liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma and teratoma; Lung:bronchogenic carcinoma (squamous cell, undifferentiated small cell,undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar)carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatoushamartoma, mesothelioma; Gastrointestinal: esophagus (squamous cellcarcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach(carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma,insulinoma, glucagonoma, gastrinoma, carcinoid tumors, vipoma), smallbowel (adenocarcinoma, lymphoma, carcinoid tumors, Kaposi's sarcoma,leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large bowel(adenocarcinoma, tubular adenoma, villous adenoma, hamartoma,leiomyoma); Genitourinary tract: kidney (adenocarcinoma, Wilm's tumor(nephroblastoma), lymphoma, leukemia), bladder and urethra (squamouscell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate(adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonalcarcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cellcarcinoma, fibroma, fibroadenoma, adenomatoid tumors, lipoma); Liver:hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma,angiosarcoma, hepatocellular adenoma, hemangioma; Biliary tract: gallbladder carcinoma, ampullary carcinoma, cholangiocarcinoma; Bone:osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibroushistiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma(reticulum cell sarcoma), multiple myeloma, malignant giant cell tumorchordoma, osteochronfroma (osteocartilaginous exostoses), benignchondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma andgiant cell tumors; Nervous system: skull (osteoma, hemangioma,granuloma, xanthoma, osteitis deformans), meninges (meningioma,meningiosarcoma, gliomatosis), brain (astrocytoma, medulloblastoma,glioma, ependymoma, germinoma (pinealoma), glioblastoma multiform,oligodendroglioma, schwannoma, retinoblastoma, congenital tumors),spinal cord neurofibroma, meningioma, glioma, sarcoma); Gynecological:uterus (endometrial carcinoma), cervix (cervical carcinoma, pre-tumorcervical dysplasia), ovaries (ovarian carcinoma (serouscystadenocarcinoma, mucinous cystadenocarcinoma, unclassifiedcarcinoma), granulosa-thecal cell tumors, Sertoli-Leydig cell tumors,dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma,intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma),vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma(embryonal rhabdomyosarcoma), fallopian tubes (carcinoma); Hematologic:blood (myeloid leukemia (acute and chronic), acute lymphoblasticleukemia, chronic lymphocytic leukemia, myeloproliferative diseases,multiple myeloma, myelodysplastic syndrome), Hodgkin's disease,non-Hodgkin's lymphoma (malignant lymphoma); Skin: malignant melanoma,basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, molesdysplastic nevi, lipoma, angioma, dermatofibroma, keloids, psoriasis;and Adrenal glands: neuroblastoma. In certain embodiments, the cancer isnon-small cell lung cancer.

The concentration and route of administration to the patient will varydepending on the cancer to be treated. The compounds, pharmaceuticallyacceptable salts thereof and pharmaceutical compositions comprising suchcompounds and salts also may be co-administered with otheranti-neoplastic compounds, e.g., chemotherapy, or used in combinationwith other treatments, such as radiation or surgical intervention,either as an adjuvant prior to surgery or post-operatively.

Also provided herein is a compound of Formula (I), Formula I-A, orFormula I-B, or a pharmaceutically acceptable salt or solvate thereof,or a pharmaceutical composition thereof as defined herein for use intherapy.

Also provided herein is a compound of Formula (I), Formula I-A, orFormula I-B, or a pharmaceutically acceptable salt or solvate thereof ora pharmaceutical composition thereof as defined herein for use in thetreatment of cancer.

Also provided herein is a compound of Formula (I), Formula I-A, orFormula I-B, or a pharmaceutically acceptable salt or solvate thereoffor use in the inhibition of KRas G12C.

Also provided herein is a compound of Formula (I), Formula I-A, orFormula I-B, or a pharmaceutically acceptable salt or solvate thereof ora pharmaceutical composition thereof as defined herein, for use in thetreatment of a KRas G12C-associated disease or disorder.

Also provided herein is the use of a compound of Formula (I), FormulaI-A, or Formula I-B, or a pharmaceutically acceptable salt or solvatethereof, as defined herein in the manufacture of a medicament for thetreatment of cancer.

Also provided herein is a use of a compound of Formula (I), Formula I-A,or Formula I-B, or a pharmaceutically acceptable salt or solvatethereof, as defined herein in the manufacture of a medicament for theinhibition of activity of KRas G12C.

Also provided herein is the use of a compound of Formula (I), FormulaI-A, or Formula I-B, or a pharmaceutically acceptable salt or solvatethereof, as defined herein, in the manufacture of a medicament for thetreatment of a KRas G12C-associated disease or disorder.

Also provided herein is a method for treating cancer in a patient inneed thereof, the method comprising (a) determining that cancer isassociated with a KRas G12C mutation (e.g., a KRas G12C-associatedcancer) (e.g., as determined using a regulatory agency-approved, e.g.,FDA-approved, assay or kit); and (b) administering to the patient atherapeutically effective amount of a compound of Formula (I), FormulaI-A, or Formula I-B, or a pharmaceutically acceptable salt thereof, or apharmaceutical composition thereof.

One skilled in the art will recognize that, both in vivo and in vitrotrials using suitable, known and generally accepted cell and/or animalmodels are predictive of the ability of a test compound to treat orprevent a given disorder.

One skilled in the art will further recognize that human clinical trialsincluding first-in-human, dose ranging and efficacy trials, in healthypatients and/or those suffering from a given disorder, may be completedaccording to methods well known in the clinical and medical arts.

Reaction Schemes and Examples

The compounds of the present invention may be prepared from commerciallyavailable reagents using the synthetic methods and reaction schemesdescribed herein, or using other reagents and conventional methods wellknown to those skilled in the art.

For instance, compounds of the present invention may be preparedaccording to the General Reaction Schemes I and II.

General Reaction Schemes

Compounds of Formula I wherein L and Y are bonds, R² is hydrogen and R⁴is aryl or heteroaryl can be prepared according to Scheme I. In step A,an appropriately functionalized dihydropyridopyrimidine (1) is coupledto a heterocycle containing one nucleophilic amine species, with theother bound to a protecting group to provide compound (2). This couplingproceeds in a solvent such as dichloromethane in the presence of a basesuch as triethylamine or Hunig's base. In step B, the Boc group ofcompound (2) is removed using conditions known in the art, for examplewith trifluoroacetic acid in a solvent such as dichloromethane, toprovide compound (3). In step C, the substituent R⁴ is introduced with apalladium coupling, using a suitable functionalized aryl or heteroarylsystem, for example an aryl triflate, in the presence of a palladiumcatalyst such as Pd2DBA3/Xantphos in a solvent such as toluene with abase such as sodium tert-butoxide to provide compound (4). In step D,the protecting group of ring X compound (4) is removed, for examplehydrogenolysis by Pd/C in the presence of H₂ in a polar solvent such asEtOH/THF to provide compound (5). In the final step, E, R¹ is introducedto provide a compound of Formula I, for example by treating with an acidchloride having the formula Cl—C(O)C(R^(A))

C(R^(B))_(p) or Cl—SO₂C(R^(A))

(R^(B))_(p), or an anhydride having the formula C(R^(B))_(p)

C(R^(A))C(O)OC(O)C(R^(A))

C(R^(B))_(p), where R^(A), R^(B) defined for Formula I. For example, inthe case where R¹ is an acryloyl group, this reaction proceeds, forexample, in a solvent such as methylene chloride in the presence ofacryloyl chloride or an acryloyl anhydride and a base such as Hunig'sbase. In some cases, the species R⁴ will also contain a protectinggroup, which can be removed at a subsequent step in the syntheticsequence.

Compounds (1), (2), (3), (4) and (5) as shown and described above forScheme 1 are useful as intermediates for preparing compounds of FormulaI and are provided as further aspects of the invention.

Compounds of Formula I wherein L is a bond, —Y—R² is other than hydrogenand R⁴ is aryl or heteroaryl can be prepared according to Scheme II. Instep A, an appropriately functionalized dihydropyridopyrimidine (6) iscoupled to a heterocycle containing one nucleophilic amine species, withthe other bound to a protecting group to provide compound (7). Thiscoupling proceeds in a solvent such as dichloromethane in the presenceof a base such as triethylamine or Hunig's base. In step B, thesubstituent —Y—R² is introduced by substitution of the chlorine by anucleophile, for example (S)-1-(dimethylamino-propan-2-ol in a polarsolvent such as dioxane to provide compound (8). In step C, the Bocgroup is removed using conditions known in the art, for example withtrifluoroacetic acid in a solvent such as dichloromethane to providecompound (9). In step D, the substituent R⁴ is introduced with apalladium coupling, using a suitable functionalized aryl or heteroarylsystem, for example an aryl triflate, in the presence of a palladiumcatalyst such as Pd₂DBA₃/BINAP in a solvent such as toluene with a basesuch as sodium tert-butoxide to provide compound (10). In step E, theprotecting group of ring X is removed, for example hydrogenolysis byPd/C in the presence of H₂ in a polar solvent such as EtOH/THF toprovide compound (11). In step F, R¹ is introduced to provide a compoundof Formula I, for example by treating with an acid chloride having theformula Cl—C(O)C(R^(A))

C(R^(B))_(p) or Cl—SO₂C(R^(A))

C(R^(B))_(p), or an anhydride having the formula C(R^(B))_(p)

C(R^(A))C(O)OC(O)C(R^(A))

C(R^(B))_(p), where R^(A), R^(B) and p areas defined for Formula I. Forexample, in the case where R¹ is an acryloyl group, this reactionproceeds, for example, in a solvent such as methylene chloride in thepresence of acryloyl chloride acryloyl anhydride and a base such asHunig's base. In some cases, the species R⁴ and R² may also containprotecting groups, which can be removed at a subsequent step in thesynthetic sequence.

Compounds (6), (7), (8), (9), (10) and (11) as shown and described abovefor Scheme 2 are useful as intermediates for preparing compounds ofFormula I, Formula I-A or Formula I-B and are provided as furtheraspects of the invention.

Accordingly, also provide is a process for preparing a compound ofFormula I, comprising:

(a) for a compound of Formula I where Y is a bond and R² is hydrogen,reacting a compound of formula 5

where X, R³ and R⁴ are as defined for Formula I, with an acid chloridehaving the formula Cl—C(O)C(R^(A))

C(R^(B))_(p) or Cl—SO₂C(R^(A))

C(R^(B))_(p) or an anhydride having the formula C(R^(B))_(p)

C(R^(A))C(O)OC(O)C(R^(A))

C(R^(B))_(p), where R^(A), R^(B) and p areas defined for Formula I, inthe presence of a base; or

(b) for a compound of Formula I wherein L is a bond and —Y—R² is otherthan hydrogen, reacting a compound of formula (11)

wherein L is a bond, —Y—R² is other than hydrogen, and X, R³ and R⁴ areas defined for Formula I, with an acid chloride having the formulaCl—C(O)C(R^(A))

C(R^(B))_(p) or Cl—SO₂C(R^(A))

C(R^(B)), or an anhydride having the formula C(R^(B))_(p)

C(R^(A))C(O)OC(O)C(R^(A))

C(R^(B))_(p), where R^(A), R^(B) and p are as defined for Formula I, inthe presence of a base; and

optionally forming a salt thereof.

The compounds of the present invention may have one or more chiralcenter and may be synthesized as stereoisomeric mixtures, isomers ofidentical constitution that differ in the arrangement of their atoms inspace. The compounds may be used as mixtures or the individualcomponents/isomers may be separated using commercially availablereagents and conventional methods for isolation of stereoisomers andenantiomers well-known to those skilled in the art, e.g., usingCHIRALPAK® (Sigma-Aldrich) or CHIRALCEL® (Diacel Corp) chiralchromatographic HPLC columns according to the manufacturer'sinstructions. Alternatively, compounds of the present invention may besynthesized using optically pure, chiral reagents and intermediates toprepare individual isomers or enantiomers. Unless otherwise indicated,all chiral (enantiomeric and diastereomeric) and racemic forms arewithin the scope of the invention. Unless otherwise indicated, wheneverthe specification, including the claims, refers to compounds of theinvention, the term “compound” is to be understood to encompass allchiral (enantiomeric and diastereomeric) and racemic forms.

The following Examples are intended to illustrate further certainembodiments of the invention and are not intended to limit the scope ofthe invention.

Intermediate 1

3-(methoxymethoxy)naphthalen-1-yl trifluoromethanesulfonate

3-Hydroxynaphthalen-1-yl trifluoromethanesulfonate (13.101 g, 44.831mmol) was dissolved in dichloromethane (100 mL) and stirred at 0° C. Tothis solution was added chloro(methoxy)methane (3.7456 ml, 49.315 mmol)and Hunig's base (11.745 mL, 67.247 mmol). The reaction was stirred at0° C. for 4 hrs. The reaction was partitioned with 1M HCl and washedwith saturated sodium bicarbonate. The combined organic layers weredried over magnesium sulfate and concentrated under vacuum. Theconcentrated material was loaded onto a 120 g RediSep® gold silica gelcolumn with dichloromethane and purified by normal phase chromatography(CombiFlash®, 0%-20% ethyl acetate/hexanes as the eluent) to give3-(methoxymethoxy)naphthalen-1-yl trifluoromethanesulfonate (11.785 g,35.045 mmol, 78.171% yield).

Intermediate 2

2-bromo-7-(methoxymethoxy)naphthalene

To a solution of 7-bromonaphthalen-2-ol (2.0 g, 9.0 mmol) in dimethylacetamide (40 mL) was added chloro(methoxy)methane (1.4 g, 18 mmol) andcesium carbonate (5.8 g, 18 mmol) and the reaction mixture was stirredovernight at room temperature. The reaction was diluted with water andthe aqueous layer washed with ethyl acetate. The combined organic layerswere washed with water and brine, dried over magnesium sulfate andconcentrated under vacuum. The crude material was purified by normalphase chromatography using 5-50% ethyl acetate/hexanes as the eluent togive 2-bromo-7-(methoxymethoxy)naphthalene (1.0 g, 3.7 mmol, 42% yield).

Intermediate 3

2-bromo-1-fluoro-3-(methoxymethyl)benzene

To a stirred solution of 2-bromo-3-fluorophenol (1422 mg, 7.445 mmol) in22 mL tetrahydrofuran at room temperature under nitrogen was added NaH(327.6 mg, 8.190 mmol) neat as a solid portion wise. After 15 minutes, asolution had formed. Chloro(methoxy)methane (678.6 μL, 8.934 mmol) wasadded by syringe. After stirring for 2 hours, the reaction was quenchedwith saturated ammonium chloride solution and then partitioned betweenethyl acetate (30 mL) and water (30 mL). The combined organic layerswere isolated, washed with brine, dried over MgSO₄, filtered andconcentrated. The crude product was loaded in a minimum ofdichloromethane onto a 40 gram RediSep® column pre-wet with hexanes andeluted with an ethyl acetate/hexanes gradient (0% to 20% ethyl acetate).Fractions containing the product were combined and concentrated toprovide the product as a clear oil (1.45 g, 83%).

Intermediate 4

2-bromo-1-fluoro-4-(methoxymethoxy)benzene

To a stirred solution of 3-bromo-4-fluorophenol (327 mg, 1.71 mmol) in5.1 mL tetrahydrofuran at room temperature under nitrogen was added NaH(75.3 mg, 1.88 mmol) neat as a solid portion wise. After 15 minutes, asolution had formed. Chloro(methoxy)methane (156 μL, 2.05 mmol) wasadded by syringe. After stirring for 2 hours, the reaction was quenchedwith saturated ammonium chloride solution and partitioned between ethylacetate and water. The combined organic layers were washed with brine,dried over MgSO₄, filtered and concentrated. The crude product wasloaded in a minimum of dichloromethane onto a 24 gram RediSep® columnpre-wet with hexanes and eluted with an ethyl acetate/hexanes gradient(0% to 20% ethyl acetate). Fractions containing the product werecombined and concentrated to provide the product as a clear oil (120 mg,29.8%) Intermediate 5

4-bromo-5-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole

To a solution of 4-bromo-5-methyl-1H-indazole (0.7 g, 3.3 mmol) indimethyl acetamide (30 mL) cooled to 0° C. was added NaH (0.19 g, 4.6mmol) in portions and the reaction mixture was purged with nitrogen. Thereaction was stirred for 20 minutes, and then(2-(chloromethoxy)ethyl)trimethylsilane (0.83 g, 5.0 mmol) was added andthe reaction was stirred for 2 hours while warming to room temperature.The reaction was quenched by pouring into water and the aqueous layerwas extracted into ethyl acetate. The combined organic layers werewashed with water and brine, dried over MgSO₄ and concentrated undervacuum. The crude material was purified by chromatography using 10-50%ethyl acetate/hexanes as the eluent to give4-bromo-5-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole (0.87g, 79%).

Intermediate 6

(R)-1-(pyrrolidin-1-yl)propan-2-ol

In a sealed tube, R-(+)-Propylene oxide (3.69 mL, 52.7 mmol) was cooledto −78° C. and then sparged with anhydrous dimethyl amine for a fewminutes. The reaction mixture was heated to 70° C. for 16 hours. Thereaction was cooled and concentrated in vacuo for 20 minutes to provide(R)-1-(pyrrolidin-1-yl)propan-2-ol (5.35 g, 41.4 mmol, 98.2% yield).

Intermediate 7

(R)-1-morpholinopropan-2-ol

In a sealed tube, R-(+)-Propylene oxide (2.111 mL, 30.13 mmol) andmorpholine (1.490 mL, 17.22 mmol) were heated to 70° C. for 20 hours.The reaction was cooled and concentrated in vacuo to provide(R)-1-morpholinopropan-2-ol (2.47 g, 17.01 mmol, 98.80% yield).

Intermediate 8

(R)-1-(dimethylamino)butan-2-ol

In a sealed tube, R-(+)-Propylene oxide (4.00 g, 55.5 mmol) anddimethylamine (1.00 g, 22.2 mmol), were heated to 65° C. for 18 hours.The reaction was cooled and concentrated in vacuo. The resulting residuewas purified by silica gel (0-12% MeOH in DCM) to provide(R)-1-(dimethylamino)butan-2-ol (1.38 g, 11.8 mmol, 53.1% yield).

Intermediate 9

(R)-1-((R)-3-methoxypyrrolidin-1-yl)propan-2-ol

In a sealed tube, (R)-3-methoxypyrrolidine hydrochloride (1.00 g, 7.27mmol), TEA (2.03 mL, 14.5 mmol) and R-(+)-Propylene oxide (1.27 mL, 18.2mmol) were heated to 65° C. for 18 hours. The reaction was cooled andconcentrated in vacuo. The resulting residue was purified by silica gel(0-12% MeOH in DCM) to provide(R)-1-((R)-3-methoxypyrrolidin-1-yl)propan-2-ol (775 mg, 4.87 mmol,67.0% yield).

Intermediate 10

(R)-1-((S)-3-methoxypyrrolidin-1-yl)propan-2-ol

In a sealed tube, (S)-3-methoxypyrrolidine hydrochloride (1.00 g, 7.27mmol), TEA (2.03 mL, 14.5 mmol) and R-(+)-Propylene oxide (1.27 mL, 18.2mmol) were heated to 65° C. for 18 hours. The reaction was cooled andconcentrated in vacuo. The resulting residue was purified by silica gel(0-12% MeOH in DCM) to provide(R)-1-((S)-3-methoxypyrrolidin-1-yl)propan-2-ol (781 mg, 4.90 mmol,67.5% yield)

Intermediate 11

(R)-1-((S)-3-((tert-butyldimethylsilyl)oxy)pyrrolidin-1-yl)propan-2-ol

In a sealed tube, R-(+)-Propylene oxide (0.609 mL, 8.69 mmol) and(S)-3-((tert-butyldimethylsilyl)oxy)pyrrolidine (1.00 g, 4.97 mmol) wereheated to 70° C. for 20 hours. The reaction was cooled and concentratedin vacuo to provide(R)-1-((S)-3-((tert-butyldimethylsilyl)oxy)pyrrolidin-1-yl)propan-2-ol(1.29 g, 4.20 mmol, 84.6% yield).

Intermediate 12

Tert-butyl 2-(hydroxymethyl)-4-methylpiperazine-1-carboxylate

To a suspension of lithium chloride (246 mg, 5.81 mmol) and LithiumBorohydride (126 mg, 5.81 mmol) in ethanol (9 mL), at 0° C. undernitrogen, a solution of 1-(tert-butyl) 2-methyl4-methylpiperazine-1,2-dicarboxylate (750 mg, 2.90 mmol) in dry THE (6mL) was added dropwise. The reaction was stirred overnight forming awhite precipitate. The precipitate was filtered and washed with ethanol.The combined filtrate and organic extracts were concentrated to providea white residue which was extracted with ethyl acetate. The combinedorganic layers were washed with saturated sodium chloride solution,dried over sodium sulfate and concentrated in vacuo. The residue waspurified by chromatography with isocratic 10% MeOH in DCM with 0.2%NH₄OH to provide tert-butyl2-(hydroxymethyl)-4-methylpiperazine-1-carboxylate (104 mg, 0.452 mmol,15.6% yield).

Intermediate 13

(S)-2-(2-methylpiperidin-1-yl)ethan-1-ol

A mixture of (S)-2-methylpiperidine (100 mg, 1.01 mmol), 2-bromoethanol(78 μL, 139 mg, 1.11 mmol, 1.1 eq.), sodium iodide (151 mg, 1 eq.),potassium carbonate (418 mg, 3 eq.) and acetonitrile (1 mL) in a 4-mLvial was purged with nitrogen, sealed and stirred at room temperaturefor 2 days. The reaction mixture was partitioned between diethyl ether(15 mL) and water (2 mL). The ether layer was washed with brine (2 mL),acidified with TFA and dried under high vacuum for 2 days. The residuewas washed with ether (3 mL), diluted with water (0.5 mL) and basifiedwith 10M NaOH (0.2 mL). The layers were separated and the upper layerwas carefully dried over NaOH. The ether solution was evaporated undernitrogen to yield crude (S)-2-(2-methylpiperidin-1-yl)ethan-1-ol (100mg, 0.698 mmol, 69.24% yield) as colorless oil.

Intermediate 14

(R)-2-(2-methylpiperidin-1-yl)ethan-1-ol

Synthesized according to the method of Intermediate 13, using(R)-2-methylpiperidine (99 mg, 1 mmol) in place of(S)-2-methylpiperidine.

Intermediate 15

(S)-2-(3-methoxypiperidin-1-yl)ethan-1-ol

Synthesized according to the method of Intermediate 13, using(S)-3-methoxypiperidine (173 mg, 1.50 mmol) in place of(S)-2-methylpiperidine.

Intermediate 16

(R)-2-(3-methoxypiperidin-1-yl)ethan-1-ol

Synthesized according to the method of Intermediate 13, usingR-3-methoxypiperidine (173 mg, 1.50 mmol) in place of(S)-2-methylpiperidine.

Intermediate 17

3-(1,4-oxazepan-4-yl)propan-1-ol

To a vial was added homomorpholine (0.250 g, 2.472 mmol), Acetonitrile(4.943 mL, 2.472 mmol) and 3-Bromo-1-propanol (0.2459 mL, 2.719 mmol).Potassium carbonate (0.6832 g, 4.943 mmol) was added and the mixture waswarmed to 50° C. and stirred for 6 hours. The mixture was cooled toambient temperature, diluted with DCM, filtered and the collected solidswere washed with DCM. The filtrate was concentrated in vacuo and thecrude oil was purified via column chromatography (Biotage Isolera, 12 gIsco RediSep Gold, 10-20% MeOH/DCM with 0.2% NH₄OH) to afford3-(1,4-oxazepan-4-yl)propan-1-ol (0.272 g, 1.708 mmol) as a colorlessoil.

Intermediate 18

3-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)propan-1-ol

Synthesized according to the method of Intermediate 17, using(1S,4S)-2-Oxa-5-azabicyclo[2.2.1]heptane (0.250 g, 2.522 mmol) in placeof homomorpholine.

Intermediate 19

2-(4-methoxypiperidin-1-yl)ethan-1-ol

Synthesized according to the method of Intermediate 13, using4-methoxypiperidine (173 mg, 1.50 mmol) in place of(S)-2-methylpiperidine.

Intermediate 20

2-(4,4-difluoropiperidin-1-yl)ethan-1-ol

Synthesized according to the method of Intermediate 13, using4,4-difluoropiperidine hydrochloride (173 mg, 1.50 mmol) in place of(S)-2-methylpiperidine.

Intermediate 21

(S)-2-(3-fluoropiperidin-1-yl)ethan-1-ol

Synthesized according to the method of Intermediate 13, usingS-3-fluoropiperidine hydrochloride (209 mg, 1.50 mmol) in place of(S)-2-methylpiperidine.

Intermediate 22

Benzyl4-(7-(3-(benzyloxy)naphthalen-1-yl)-2-(methylsulfinyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylateStep A: tert-butyl4-hydroxy-2-(methylthio)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate

To a stirred solution of 1-tert-butyl 4-ethyl3-oxopiperidine-1,4-dicarboxylate (50.0 g, 184 mmol, 1.00 eq) in MeOH(1.00 L) at 25° C. under nitrogen was added NaOMe (49.8 g, 921 mmol,5.00 eq), followed by 2-methylisothiourea (62.4 g, 331 mmol, 1.80 eq,H₂SO₄) as a solid. The reaction mixture was stirred at 25° C. for 16hours. The reaction mixture was adjusted to pH 5 with HCl (2 M), and themixture was concentrated under reduced pressure to removed MeOH. Theresidue was suspended in 300 mL of ethyl acetate and 300 mL of water andstirred rapidly. The suspension was filtered and the white solid wascollected. The filtrate was separated and the organic layer was washedwith water (1×300 mL) and brine (1×200 mL). The combined organic layerswere isolated, dried over Na₂SO₄, filtered and concentrated to providetert-butyl4-hydroxy-2-methylsulfanyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate(51.0 g, 138 mmol, 75.4% yield, 81.0% purity) as a white solid which asused directly in the next step without further purification. ESI MS m/z298.2 [M+H]⁺.

Step B: tert-butyl2-methylsulfanyl-4-(trifluoromethylsulfonyloxy)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate

To a stirred suspension of tert-butyl4-hydroxy-2-methylsulfanyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate(51.0 g, 171 mmol, 1.00 eq) in DCM (500 mL) at 0° C. was added DIEA(44.3 g, 343 mmol, 59.9 mL, 2.00 eq), followed bytrifluoromethanesulfonic anhydride (72.6 g, 257 mmol, 42.4 mL, 1.50 eq)under nitrogen. Immediately a brown solution formed. After stirring at25° C. for 16 hours, the reaction was concentrated to give a brown oil.The brown oil was purified by column chromatography (SiO₂, Petroleumether/Ethyl acetate=1:0 to 10:1) to provide tert-butyl2-methylsulfanyl-4-(trifluoromethylsulfonyloxy)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate(46.0 g, 107 mmol, 62.4% yield) as a yellow solid ESI MS m/z 430.2[M+H]⁺.

Step C: tert-butyl4-(4-benzyloxycarbonylpiperazin-1-yl)-2-methylsulfanyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate

To a stirred solution of tert-butyl2-methylsulfanyl-4-(trifluoromethylsulfonyloxy)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate(46.0 g, 107 mmol, 1.00 eq) in DMF (500 mL) was added DIEA (27.7 g, 214mmol, 37.4 mL, 2.00 eq) followed by benzyl piperazine-1-carboxylate(25.9 g, 117 mmol, 22.7 mL, 1.10 eq). The reaction was heated to 100° C.for 1 hour under a nitrogen atmosphere. The reaction mixture was pouredinto ethyl acetate (300 mL), washed with H₂O (300 mL×3) and brine (200mL), dried over anhydrous Na₂SO₄, filtered and concentrated undervacuum. The residue was purified by column chromatography (SiO₂,Petroleum ether/Ethyl acetate=1:0 to 5:1) to give tert-butyl4-(4-benzyloxycarbonylpiperazin-1-yl)-2-methylsulfanyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate(51.0 g, 96.9 mmol, 90.5% yield, 92.0% purity) as a white solid ESI MSm/z 500.3 [M+H]⁺.

Step D: Benzyl4-(2-methylsulfanyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate

To a solution of tert-butyl4-(4-benzyloxycarbonylpiperazin-1-yl)-2-methylsulfanyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate(25.0 g, 50.0 mmol, 1.00 eq) in DCM (50.0 mL) was added TFA (85.6 g, 750mmol, 55.6 mL, 15.0 eq). After stirring at 25° C. for 1 hour, thereaction mixture was concentrated under reduced pressure. The residuewas dissolved in 300 mL of ethyl acetate and 300 mL of water and stirredrapidly. The mixture was adjusted to pH 8 with Na₂CO₃. The organic layerwas washed with water (1×300 mL) and brine (1×200 mL), dried overNa₂SO₄, filtered and concentrated under reduced pressure to providebenzyl4-(2-methylsulfanyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate (19.0 g, 46.6 mmol, 93.2% yield, 98.0% purity)as a yellow oil. ESI MS m/z 400.2 [M+H]⁺.

Step E: Benzyl4-[7-(3-benzyloxy-1-naphthyl)-2-methylsulfanyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate

A mixture of 3-benzyloxy-1-bromo-naphthalene (16.3 g, 52.1 mmol, 1.30eq), benzyl4-(2-methylsulfanyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(16.0 g, 40.1 mmol, 1.00 eq), Cs₂CO₃ (32.6 g, 100 mmol, 2.50 eq),Pd₂(dba)₃ (5.50 g, 6.01 mmol, 0.15 eq) and2-dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl (RuPhos) (3.74 g,8.01 mmol, 0.20 eq) in dioxane (300 mL) was degassed and purged withnitrogen 3 times. The mixture was stirred at 85° C. for 5 hours under anitrogen atmosphere. The reaction mixture was quenched by adding water(200 mL) at 0° C., and extracted with ethyl acetate (3×200 mL). Thecombined organic layers were washed with brine (3×150 mL), dried overNa₂SO₄, filtered and concentrated under reduced pressure. The residuewas purified by column chromatography (SiO₂, DCM/MeOH=10/1 to 5/1) toprovide benzyl4-[7-(3-benzyloxy-1-naphthyl)-2-methylsulfanyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(16.0 g, 22.8 mmol, 56.9% yield, 90.0% purity) as a yellow solid. ESI MSm/z 632.5 [M+H]⁺.

Step F: Benzyl4-[7-(3-benzyloxy-1-naphthyl)-2-methylsulfinyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate

To a stirred solution of benzyl4-[7-(3-benzyloxy-1-naphthyl)-2-methylsulfanyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(8.00 g, 12.7 mmol, 1.00 eq) in DCM (200 mL) was added m-CPBA (2.73 g,12.7 mmol, 80.0% purity, 1.00 eq) at 0° C. under nitrogen. Afterstirring at 0° C. for 2 hours under a nitrogen atmosphere, the reactionmixture was quenched by adding Na₂S₂O₃ (10.0 mL) at 0° C., diluted withwater (100 mL) and extracted with DCM (200 mL). The combined organiclayers were washed with brine (200 mL), dried over Na₂SO₄, filtered andconcentrated under reduced pressure to give a residue. The residue waspurified by column chromatography (SiO₂, DCM/MeOH=1/0 to 10/1) toprovide benzyl4-[7-(3-benzyloxy-1-naphthyl)-2-methylsulfinyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate (3.50 g, 4.92 mmol, 38.8%yield, 91.0% purity) as a yellow solid. ESI MS m/z 648.5 [M+H]+.

Intermediate 23

(R)-1-(4-(2-hydroxypropyl)piperazin-1-yl)ethan-1-one Step A:1-[4-[(2R)-2-hydroxypropyl]piperazin-1-yl]ethanone

(2R)-2-methyloxirane (1.00 g, 17.2 mmol, 1.20 mL, 1.00 eq) and1-piperazin-1-ylethanone (8.00 g, 62.4 mmol, 3.62 eq) were taken up intoa microwave tube. The sealed tube was heated at 150° C. for 1 hour undermicrowave. The mixture was dissolved in DCM (80.0 mL), added (Boc)₂O(3.62 eq, 13.6 g) and stirred at 20° C. for 1 hour. The residue waspurified by column chromatography (DCM/MeOH 100/1 to 10/1) to give1-[4-[(2R)-2-hydroxypropyl]piperazin-1-yl]ethanone (3.80 g, 13.5 mmol,78.2% yield, 66.0% purity) as a yellow oil.

Intermediate 24

1-(benzyloxy)-3-bromo-5-cyclopropylbenzene

Step A: 1-benzyloxy-3,5-dibromo-benzene

To a mixture of 3,5-dibromophenol (1.50 g, 5.95 mmol, 1.00 eq) and K₂CO₃(2.47 g, 17.9 mmol, 3.00 eq) in MeCN (30.0 mL) was added benzyl bromide(1.07 g, 6.25 mmol, 742 μL, 1.05 eq), the reaction mixture was stirredat 80° C. for 2 hours. The reaction mixture was filtered andconcentrated. The residue was purified by column chromatography (SiO₂,Petroleum ether/Ethyl acetate=1:1 to give 1-benzyloxy-3,5-dibromobenzene(1.60 g, 4.68 mmol, 78.6% yield) as colorless oil.

Step B: 1-benzyloxy-3-bromo-5-cyclopropylbenzene

To a mixture of 1-benzyloxy-3,5-dibromobenzene (1.20 g, 3.51 mmol, 1.00eq) and cyclopropylboronic acid (392 mg, 4.56 mmol, 1.30 eq) in H₂O(4.00 mL) and dioxane (20.0 mL) was added Pd(dppf)Cl₂ (513 mg, 702 μmol,0.20 eq) and Cs₂CO₃ (2.29 g, 7.02 mmol, 2.00 eq). The reaction mixturewas stirred at 90° C. for 12 hours under N₂. The reaction mixture wasadded to water (20 mL) and extracted with ethyl acetate (2×15 mL). Thecombined organic layers were dried over Na₂SO₄, filtered andconcentrated. The residue was purified by column chromatography (SiO₂,Petroleum ether/Ethyl acetate=1:1 to give1-benzyloxy-3-bromo-5-cyclopropyl-benzene (270 mg, 890 μmol, 25.4%yield) as colorless oil.

Intermediate 25

Benzyl4-(2-(3-morpholinopropoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylateStep A: tert-butyl4-(4-benzyloxycarbonylpiperazin-1-yl)-2-(3-morpholinopropoxy)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate

To a mixture of 3-morpholinopropan-1-ol (5.46 g, 37.6 mmol, 2.00 eq) inTHE (100 mL) was added NaH (2.26 g, 56.4 mmol, 60.0% purity, 3.00 eq) inportions at 0° C. After the mixture was stirred at 0° C. for 0.5 hour, asolution of tert-butyl4-(4-benzyloxycarbonylpiperazin-1-yl)-2-methylsulfonyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate(10.0 g, 18.8 mmol, 1.00 eq) in THE (100 mL) was added, and the reactionmixture was stirred at 0° C. for 1.5 hours under N₂. The mixture waspoured into NH₄Cl aqueous (300 mL), and extracted with DCM (2×200 mL).The combined organic layers were dried over Na₂SO₄, filtered andconcentrated. The residue was purified by column chromatography (SiO₂,Petroleum ether/Ethyl acetate=50:1 to 10:1) to give tert-butyl4-(4-benzyloxycarbonylpiperazin-1-yl)-2-(3-morpholinopropoxy)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate(7.70 g, 12.8 mmol, 67.8% yield, 98.8% purity) as a yellow oil. ESI MSm/z 597.4 [M+H]+.

Step B: benzyl4-[2-(3-morpholinopropoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate

To a mixture of tert-butyl4-(4-benzyloxycarbonylpiperazin-1-yl)-2-(3-morpholinopropoxy)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate(7.70 g, 12.9 mmol, 1.00 eq) in DCM (80.0 mL) was added TFA (119 g, 1.04mol, 76.9 mL, 80.6 eq), and the reaction mixture was stirred at 15° C.for 1 hour. The reaction mixture was concentrated, then diluted with DCM(100 mL) and adjusted to pH 8 with aqueous NaOH. The organic layer wasseparated, dried over Na₂SO₄, filtered and concentrated to give benzyl4-[2-(3-morpholinopropoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(6.00 g, 11.2 mmol, 86.9% yield, 92.8% purity) as yellow oil. ESI MS m/z497.4 [M+H]⁺.

Intermediate 26

4-(benzyloxy)-2-bromo-1-fluorobenzene

To a solution of 3-bromo-4-fluorophenol (4.00 g, 20.9 mmol, 1.00 eq) andK₂CO₃ (8.68 g, 62.8 mmol, 3.00 eq) in ACN (80.0 mL) was added benzylbromide (3.65 g, 21.4 mmol, 2.54 mL, 1.02 eq) and the reaction mixturewas stirred at 60° C. for 2 hrs. The reaction mixture was filtered andconcentrated in vacuum. The residue was purified by silica gelchromatography (petroleum ether:ethyl acetate; gradient from 1:0 to10:1) to give 4-benzyloxy-2-bromo-1-fluoro-benzene (5.02 g, 17.0 mmol,81.0% yield, 95% purity) was obtained as white solid.

Intermediate 27

2-(3-fluoropyrrolidin-1-yl)ethan-1-ol Step A: Tert-butyl3-fluoropyrrolidine-1-carboxylate

To a solution of tert-butyl 3-hydroxypyrrolidine-1-carboxylate (10.0 g,53.4 mmol, 1.00 eq) in DCM (150.00 mL) was added diethylaminosulfurtrifluoride (DAST) (12.9 g, 80.1 mmol, 10.6 mL, 1.50 eq) at −40° C.under a nitrogen atmosphere. After stirring at −40° C. for 2 hours, themixture was warmed to 20° C. and stirred for 16 hours. The mixture waspoured into 5% aqueous sodium bicarbonate (200 mL) and extracted withdichloromethane (2×100 mL). The organic layer was dried over sodiumsulfate, filtered and concentrated under vacuum. The residue waspurified by column chromatography over silica gel (petroleum ether/ethylacetate 100:1 to 5:1). The desired fractions were collected andconcentrated under vacuum to give tert-butyl3-fluoropyrrolidine-1-carboxylate (4.30 g, 22.7 mmol, 42.6% yield) as acolorless oil. ¹H NMR (400 MHz, Chloroform-d) δ=5.27 (t, J=3.6 Hz,0.5H), 5.13 (t, J=3.6 Hz, 0.5H), 3.77-3.38 (m, 4H), 2.26-2.15 (m, 1H),2.08-1.85 (m, 1H), 1.46 (s, 9H).

Step B: 3-fluoropyrrolidine

To a solution of tert-butyl 3-fluoropyrrolidine-1-carboxylate (4.30 g,22.7 mmol, 1.00 eq) in DCM (50.00 mL) was added HCl/dioxane (4 M, 35.0mL, 6.16 eq) dropwise at 0° C. The mixture was warmed to 20° C. andstirred for 1 hour. The mixture was concentrated under vacuum. Theresidue was triturated with diisopropyl ether (20 mL) and theprecipitate was filtered and dried under vacuum to provide3-fluoropyrrolidine (2.70 g, 21.5 mmol, 94.6% yield, HCl) as a whitesolid. ¹H NMR (400 MHz, Methanol-d₄) δ=5.51 (t, J=3.6 Hz, 0.5H), 5.38(t, J=3.6 Hz, 1H), 3.66-3.27 (m, 5H), 2.45-2.12 (m, 2H).

Step C: Methyl 2-(3-fluoropyrrolidin-1-yl)acetate

A suspension of 3-fluoropyrrolidine (2.70 g, 21.5 mmol, 1.00 eq, HCl) inDCM (27.00 mL) was cooled to 0° C. Triethylamine (5.44 g, 53.8 mmol,7.45 mL, 2.50 eq) and methyl 2-bromoacetate (3.62 g, 23.7 mmol, 2.23 mL,1.10 eq) were added and the reaction mixture was stirred at 20° C. for16 h. The reaction mixture was diluted with CH₂Cl₂ (100 mL) and water(50 mL). The organic layer was washed with 5% aqueous citric acidsolution (1×50 mL). The water layer was basified by saturated aqueoussodium carbonate solution (20 mL) and extracted with ethyl acetate(3×100 mL). The combined organic layers were dried over sodium sulfateand concentrated in vacuo to give methyl2-(3-fluoropyrrolidin-1-yl)acetate (2.20 g, 13.7 mmol, 63.5% yield). ¹HNMR (400 MHz, Chloroform-d) 6=5.22-5.02 (m, 1H), 3.66 (s, 3H), 3.35 (s,2H), 3.07-2.93 (m, 1H), 2.91-2.77 (m, 2H), 2.67 (dt, J=5.2, 8.4 Hz, 1H),2.21-1.93 (m, 2H).

Step D: 2-(3-fluoropyrrolidin-1-yl)ethanol

To a solution of LiAlH₄ (706 mg, 18.6 mmol, 1.50 eq) in THE (20 mL) wasadded a solution of methyl 2-(3-fluoropyrrolidin-1-yl)acetate (2.00 g,12.4 mmol, 1.00 eq) in THE (10 mL) dropwise at 0° C. The mixture waswarmed up to 20° C. and stirred for 3 hours. The mixture was quenchedwith saturated aqueous sodium sulfate solution (1 mL). The mixture wasfiltered and the filtrate was concentrated under vacuum. The product waspurified by silica gel chromatography using 5% MeOH in DMC. The desiredfractions were collected and concentrated under vacuum to give2-(3-fluoropyrrolidin-1-yl)ethanol (1.20 g, 9.01 mmol, 72.6% yield) as acolorless oil. ¹H NMR (400 MHz, Chloroform-d) δ=5.28-5.05 (m, 1H),3.68-3.61 (m, 2H), 2.99-2.73 (m, 4H), 2.72-2.67 (m, 2H), 2.58-2.45 (m,1H), 2.28-1.97 (m, 2H).

Intermediate 28

1-(tert-butyl) 3-methyl piperazine-1,3-dicarboxylate Step A: Methylpiperazine-2-carboxylate

To a mixture of 1-tert-butyl 2-methyl piperazine-1,2-dicarboxylate (5.0g, 22.6 mmol, 1.00 eq) in MeOH (50.0 mL) was added HCl/dioxane (4.0 M,134 mL). The reaction mixture was degassed and purged with nitrogen 3times, and the mixture was stirred at 25° C. for 12 hours under anitrogen atmosphere. The reaction mixture was concentrated under reducedpressure to dryness to give methyl piperazine-2-carboxylate (4.89 g,2HCl, crude) as a white solid, which was used directly in the next stepwithout further purification.

Step B: 1-(tert-butyl) 3-methyl piperazine-1,3-dicarboxylate

To a solution of methyl piperazine-2-carboxylate (4.30 g, crude) and TEA(8.02 g, 79.2 mmol, 11.0 mL) in MeOH (50.0 mL) was added di-tert-butyldicarbonate (4.32 g, 19.8 mmol, 4.55 mL). After stirring at 25° C. for12 hours, the reaction mixture was filtered and concentrated underreduced pressure to dryness. The residue was purified by columnchromatography (SiO₂, DCM/MeOH=1:0 to 20:1) to give 1-(tert-butyl)3-methyl piperazine-1,3-dicarboxylate (4.80 g, 19.7 mmol, two steps,99.0% yield) as a colorless oil. ¹H NMR (400 MHz, chloroform-d)δ=4.10-3.85 (m, 1H), 3.73 (s, 3H), 3.71-3.65 (m, 1H), 3.47-3.38 (m, 1H),3.10-2.98 (m, 2H), 2.78-2.66 (m, 1H), 2.17 (s, 1H), 1.46 (s, 9H).

Intermediate 29

4-bromonaphthalen-2-ol Step A: 2,4-dibromonaphthalen-1-amine

To a solution of Br₂ (246 g, 1.54 mol, 79.3 mL, 2.18 eq) in AcOH (750mL) was added a solution of naphthalen-1-amine (101 g, 705 mmol, 99.0mL, 1.00 eq) in AcOH (500 mL) at ambient temperature, and the reactionwas stirred at 70° C. for 1 hour. The reaction mixture was cooled atroom temperature and filtered. The filter cake was washed with AcOH (300mL), then added to 20% aqueous of NaOH (1.2 L). The mixture was stirredfor 20 min and filtered. The isolated solid was washed with water (1 L)and dried under vacuum to provide 2,4-dibromonaphthalen-1-amine (200 g,664 mmol, 94.2% yield) as gray solid. ESI MS m/z 301. 9 [M+H]⁺.

Step B: 4-bromo-1-diazonio-naphthalen-2-olate

To a solution of 2,4-dibromonaphthalen-1-amine (60.0 g, 199 mmol, 1.00eq) in AcOH (900 mL) and propionic acid (150 mL) was added NaNO₂ (16.5g, 239 mmol, 13.0 mL, 1.20 eq) portionwise at 5-8° C. over 30 min, andthen the reaction mixture was stirred at 5-8° C. for 30 min. Thereaction mixture was poured into ice-water (4000 mL), and the resultingsolid was collected and washed with water (2×50 mL) to provide4-bromo-1-diazonio-naphthalen-2-olate (150 g, wet crude) as gray solidwhich was used directly in the next step. ¹H NMR (400 MHz, CDCl₃) δ8.12-8.10 (d, J=8.4 Hz, 1H), 7.62-7.58 (t, J=7.6 Hz, 1H), 7.41-7.37 (t,J=7.6 Hz, 1H), 7.31-7.29 (d, J=8.0 Hz, 1H), 7.20 (s, 1H).

Step C: 4-bromonaphthalen-2-ol

To a solution of 4-bromo-1-diazonio-naphthalen-2-olate (100 g, 402 mmol,1.00 eq) in EtOH (2.00 L) was added portionwise NaBH₄ (30.4 g, 803 mmol,2.00 eq) at 13-15° C. over 1 h, and the reaction mixture was stirred at15-18° C. for 3 hrs. The reaction was filtered and concentrated todryness. The residue was dissolved in DCM (1000 mL) and washed withwater (500 mL×2). The organic phase was dried over Na₂SO₄ andconcentrated to dryness. The residue was purified by silica gel columnchromatograph, eluting with diethyl ether/ethyl acetate (60:1 to 10:1).The isolated product was further purified by reversed phase HPLC toprovide 4-bromonaphthalen-2-ol (40.0 g, 139 mmol, 17.3% yield, 77.4%purity) as a gray solid. ¹H NMR (400 MHz, CDCl₃) δ 8.07-8.05 (d, J=8.0Hz, 1H), 7.60-7.58 (d, J=7.6 Hz, 1H), 7.41-7.36 (m, 3H), 7.07 (s, 1H).

Step D: 3-benzyloxy-1-bromo-naphthalene

A mixture of 4-bromonaphthalen-2-ol (30.0 g, 134 mmol, 1.00 eq), benzylbromide (25.3 g, 148 mmol, 17.6 mL, 1.10 eq) and K₂CO₃ (55.7 g, 403mmol, 3.00 eq) in MeCN (500 mL) was heated at 80° C. for 1 hr. Thereaction mixture was filtered and concentrated to dryness. The residuewas purified by silica gel column chromatography, eluting with diethylether/ethyl acetate (100:1 to 60:1) to provide3-benzyloxy-1-bromo-naphthalene (40.0 g, 128 mmol, 95% yield) as yellowoil. ¹H NMR (400 MHz, CDCl₃) δ 8.19-8.17 (d, J=8.0 Hz, 1H), 7.75-7.32(d, J=8.8 Hz, 1H), 7.64-7.63 (d, J=2.4 Hz, 1H), 7.52-7.37 (m, 7H),7.23-7.21 (d, J=2.0 Hz, 1H), 5.2 (s, 2H).

Intermediate 30

3-methoxynaphthalen-1-yl trifluoromethanesulfonate Step A:3-methoxynaphthalen-1-ol

To a solution of naphthalene-1,3-diol (3.00 g, 18.7 mmol, 1.00 eq) inMeOH (60.0 mL) was added HCl/MeOH (4 M, 60.0 mL, 12.8 eq) at 0° C. Themixture was stirred at 25° C. for 60 hours. The solvent was removedunder vacuum. The residue was purified by silica gel chromatography(diethyl ether:ethyl acetate=10:1 to 5:1) to give3-methoxynaphthalen-1-ol (2.10 g, 12.1 mmol, 64.4% yield) as a brownsolid. ¹H NMR (400 MHz, CDCl₃-d₆) δ=8.10-8.08 (d, J=8.4 Hz, 1H).7.73-7.71 (d, J=8.4 Hz, 1H), 7.47-7.45 (m, 1H), 7.38-7.35 (m, 1H),6.80-6.79 (d, J=2.0 Hz, 1H), 6.56-6.55 (d, J=2.4 Hz, 1H), 3.92 (s, 3H).

Step B: (3-methoxy-1-naphthyl) trifluoromethanesulfonate

To a solution of 3-methoxynaphthalen-1-ol (2.10 g, 12.0 mmol, 1.00 eq)in DCM (40.0 mL) was added DIEA (7.79 g, 60.3 mmol, 10.5 mL, 5.00 eq)and trifluoromethanesulfonic anhydride (5.10 g, 18.1 mmol, 2.98 mL, 1.50eq) at 0° C. The mixture was stirred at 25° C. for 1 hour. The mixturewas diluted with DCM (30 mL) and water (10 mL) and extracted with DCM(20 mL). The combined organic layers were washed with brine (5 mL),dried over Na₂SO₄ and concentrated under vacuum. The residue waspurified by silica gel chromatography (diethyl ether:ethyl acetate=20:1to 10:1) to give (3-methoxy-1-naphthyl) trifluoromethanesulfonate (3.00g, 8.52 mmol, 70.7% yield, 87.0% purity) as a brown oil. ESI MS m/z307.1 [M+H]⁺.

Intermediate 31

7-benzyl-2,4-dichloro-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine Step A:7-benzyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-2,4-diol

To EtOH (600 mL) was added Na (5.56 g, 241 mmol, 5.73 mL, 2.40 eq) inportions. The reaction mixture was stirred for 1 hour. To the mixturewas added ethyl 1-benzyl-3-oxo-piperidine-4-carboxylate (30.0 g, 100mmol, 1.00 eq, HCl) and urea (14.5 g, 242 mmol, 13.0 mL, 2.40 eq). Thereaction mixture was stirred at 75° C. for 36 hours, and then thesolvent was removed under vacuum. The residue was dissolved in water (50mL) and acidified with HCl (120 mL, 2M). A white solid precipitated fromthe solution and was collected by filtration. The filter cake was driedunder vacuum to provide7-benzyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-2,4-diol (22.0 g, 83.8mmol, 83.2% yield, 98% purity) as a white solid. ¹HNMR (400 MHz,DMSO-d₆) δ=10.97 (br s, 1H), 10.66 (br s, 1H), 7.55-6.95 (m, 5H),3.81-3.50 (m, 2H), 3.26-2.91 (m, 2H), 2.77-2.58 (m, 2H), 2.34-2.09 (m,2H).

Step B: 7-benzyl-2,4-dichloro-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine

To a solution of DIEA (30.1 g, 233 mmol, 40.7 mL, 3.00 eq) in POCl₃ (330g, 2.15 mol, 200 mL) was added7-benzyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-2,4-diol (20.0 g, 77.7mmol, 1.00 eq). The reaction mixture was stirred at 110° C. for 5 hours.The reaction mixture was concentrated under vacuum. The residue wasdissolved in DCM (400 mL) and poured into saturated NaHCO₃ (200 mL). Themixture was extracted with DCM (2×400 mL). The combined organic layerswere washed with brine (100 mL), dried over Na₂SO₄ and concentratedunder vacuum. The residue was purified by silica gel chromatography(diethyl ether:DCM=10:1 to 0:1) to give7-benzyl-2,4-dichloro-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine (7.70 g,26.2 mmol, 33.7% yield) as a brown oil. ¹HNMR (300 MHz, chloroform-d)6=7.43-7.28 (m, 5H), 3.73 (s, 2H), 3.66 (br s, 2H), 2.84 (br s, 4H)Intermediate 32

tert-butyl4-(4-((benzyloxy)carbonyl)piperazin-1-yl)-2-(methylsulfonyl)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylateStep A:tert-butyl4-hydroxy-2-methylsulfanyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate

To a stirred solution of 1-tert-butyl4-ethyl-3-oxopiperidine-1,4-dicarboxylate (44.0 g, 162 mmol, 1.00 eq) inMeOH (1.00 mL) at 25° C. under nitrogen was added a solution of NaOMe(35.0 g, 649 mmol, 4.00 eq) in MeOH (600 mL) by syringe followed by2-methylisothiourea (61.1 g, 324 mmol, 2.00 eq, H₂SO₄). After stirringat 25° C. for 16 hours, the reaction mixture was concentrated underreduced pressure to removed MeOH. The residue was suspended in 500 mL ofethyl acetate and 500 mL of water and stirred rapidly. The reactionmixture was adjusted to pH 5 with HCl (2 M). The precipitate wasfiltered and the white solid was washed with ethyl acetate and driedunder vacuum to givetert-butyl4-hydroxy-2-methylsulfanyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate(33.0 g, 103 mmol, 63.8% yield, 93.2% purity) as a white solid, whichwas used directly in the next step without further purification. ¹H NMR(400 MHz, DMSO-d₆) δ=4.19 (s, 2H), 3.49 (br s, 2H), 2.46 (s, 3H), 2.35(br t, J=5.2 Hz, 2H), 1.42 (s, 9H).

Step B: give tert-butyl2-methylsulfanyl-4-(trifluoromethylsulfonyloxy)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate

To a stirred suspension of tert-butyl4-hydroxy-2-methylsulfanyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate(15.0 g, 50.4 mmol, 1.00 eq) in DCM (200 mL) was added DIEA (26.1 g, 202mmol, 35.2 mL, 4.00 eq) at 0° C. under nitrogen and followed bytrifluoromethanesulfonic anhydride (28.5 g, 101 mmol, 16.6 mL, 2.00 eq)by syringe. Immediately a brown solution formed. The reaction mixturewas stirred at 25° C. for 12 hours. The reaction mixture was purified bycolumn chromatography (SiO₂, Petroleum ether/Ethyl acetate=1:0 to 10:1)to give tert-butyl2-methylsulfanyl-4-(trifluoromethylsulfonyloxy)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate (16.7 g, 35.7 mmol, 70.9% yield, 91.9%purity) as a white solid. ESI MS m/z 374.0 [M+H]⁺.

Step C: Tert-butyl4-(4-benzyloxycarbonylpiperazin-1-yl)-2-methylsulfanyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate

To a stirred solution of tert-butyl2-methylsulfanyl-4-(trifluoromethylsulfonyloxy)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate (16.7g, 38.9 mmol, 1.00 eq) in DMF (100 mL) was added DIEA (10.0 g, 77.9mmol, 2.00 eq) and benzyl piperazine-1-carboxylate (9.41 g, 42.8 mmol,1.10 eq). The reaction was heated to 100° C. and stirred for 1 hourunder a nitrogen atmosphere. The reaction mixture was diluted with water(150 mL) and the reaction mixture was adjusted to pH 5 with HCl (2 M)and extracted with DCM (3×200 mL). The combined organic layers werewashed with saturated NaHCO₃ (3×150 mL), brine (3×150 mL) and H₂O (3×150mL), dried over Na₂SO₄, filtered and concentrated under reduced pressureto give tert-butyl4-(4-benzyloxycarbonylpiperazin-1-yl)-2-methylsulfanyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate(18.1 g, 36.2 mmol, 93.0% yield, 94.1% purity) as a yellow solid, whichwas used directly in the next step without further purification. ESI MSm/z 500.1 [M+H]⁺.

Step D: tert-butyl4-(4-benzyloxycarbonylpiperazin-1-yl)-2-methylsulfonyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate

To a stirred solution oftert-butyl4-(4-benzyloxycarbonylpiperazin-1-yl)-2-methylsulfanyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate(14.4 g, 28.9 mmol, 1.00 eq) in DCM (150 mL) at 0° C. under nitrogen wasadded meta-chloroperoxybenzoic acid (17.4 g, 101 mmol, 3.50 eq) as asolid. After stirring at 0° C. for 2 hours under a nitrogen atmosphere,the reaction mixture was diluted with water (300 mL) and the reactionmixture was adjusted to pH 8 with saturated aqueous NaHCO₃ and extractedwith DCM (3×200 mL). The combined organic layers were washed with brine(3×200 mL), dried over Na₂SO₄, filtered and concentrated under reducedpressure to dryness. The residue was purified by column chromatography(SiO₂, Petroleum ether/Ethyl acetate=10:1 to 1:2) to give tert-butyl4-(4-benzyloxycarbonylpiperazin-1-yl)-2-methylsulfonyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate(11.0 g, 19.7 mmol, 68.6% yield, 95.4% purity) as a white solid. ESI MSm/z 532.1 [M+H]⁺.

Intermediate 33

Tert-butyl (1-bromoisoquinolin-3-yl)carbamate Step A

A mixture of 1-bromoisoquinolin-3-amine (400 mg, 1.79 mmol, 1.00 eq) andtert-butoxycarbonyl tert-butyl carbonate (3.91 g, 17.9 mmol, 4.12 mL,10.0 eq) was stirred at 70° C. for 16 hours. The residue was purified bycolumn chromatography (SiO₂, diethyl ether/ethyl acetate=5:1) to givetert-butyl N-(1-bromo-3-isoquinolyl) carbamate (400 mg, 1.24 mmol, 69.2%yield) as a yellow solid. ESI MS m/z 322.1, 324.1 [M+H]⁺.

Intermediate 34

3-methoxy-6-methylnaphthalen-1-yl Trifluoromethanesulfonate Step A:3-methoxynaphthalen-1-ol

To a solution of naphthalene-1,3-diol (40.0 g, 250 mmol, 1.00 eq) inMeOH (800 mL) was added HCl (4 M, 750 mL, 12.0 eq, 4 M in MeOH) at 0° C.The mixture was warmed up to 18° C. and stirred for 30 hours. Themixture was concentrated under vacuum. The residue was purified bycolumn chromatography over silica gel (petroleum ether/ethyl acetate100/1 to 1/1). The desired fractions were collected and concentratedunder vacuum to give 3-methoxynaphthalen-1-ol (17.7 g, 96.5 mmol, 38.6%yield, 95% purity) as a red oil. ¹H NMR (400 MHz, Chloroform-d) 6=8.17(d, J=8.4 Hz, 1H), 7.74 (d, J=8.0 Hz, 1H), 7.50 (ddd, J=1.2, 6.8, 8.0Hz, 1H), 7.38 (ddd, J=1.2, 6.8, 8.0 Hz, 1H), 6.81 (d, J=2.0 Hz, 1H),6.76 (br s, 1H), 6.62 (d, J=2.4 Hz, 1H), 3.91 (s, 3H).

Step B: tert-butyl-[(3-methoxy-1-naphthyl)oxy]-dimethyl-silane

To a solution of 3-methoxynaphthalen-1-ol (20.0 g, 115 mmol, 1.00 eq)and imidazole (23.5 g, 344 mmol, 3.00 eq) in THE (400 mL) was addedTBSCl (26.0 g, 172 mmol, 21.1 mL, 1.50 eq) dropwise at 0° C. The mixturewas warmed up to 25° C. and stirred for 16 hours. The mixture wasdiluted with petroleum ether (600 mL) and ethyl acetate (200 mL), andthen washed with water (1×200 mL) and brine (1×200 mL). The separatedorganic layer was dried over sodium sulfate, filtered and concentratedunder vacuum. The residue was purified by column chromatography oversilica gel (petroleum ether/ethyl acetate 100/1 to 10/1).tert-butyl-[(3-methoxy-1-naphthyl)oxy]-dimethyl-silane (28.0 g, 97.1mmol, 84.6% yield) was obtained as a colorless oil. HH NMR (400 MHz,Chloroform-d) 6=8.01 (d, J=8.4 Hz, 1H), 7.61 (d, J=8.0 Hz, 1H), 7.35(dt, J=1.2, 7.6 Hz, 1H), 7.24 (dt, J=1.2, 7.6 Hz, 1H), 6.71 (d, J=2.0Hz, 1H), 6.48 (d, J=2.4 Hz, 1H), 3.82 (s, 3H), 1.02 (s, 9H), 0.23 (s,6H).

Step C:tert-butyl-[[3-methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-naphthyl]oxy]-dimethyl-silaneandtert-butyl((3-methoxy-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)oxy)dimethylsilane

A mixture of tert-butyl-[(3-methoxy-1-naphthyl) oxy]-dimethyl-silane(26.0 g, 90.1 mmol, 1.00 eq),4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane(45.8 g, 180 mmol, 2.00 eq), (1Z,5Z)-cycloocta-1,5-diene;2,4-dimethyl-BLAHbicyclo[1.1.0]butane (2.39 g, 3.61 mmol, 0.04 eq) and4-tert-butyl-2-(4-tert-butyl-2-pyridyl)pyridine (1.45 g, 5.41 mmol, 0.06eq) in hexane (500 mL) was stirred at 100° C. under nitrogen atmospherefor 16 hours. The mixture was diluted with water (500 mL) and ethylacetate (1000 mL). The separated organic layer was washed with brine(1×500 mL), dried over sodium sulfate, filtered and concentrated undervacuum. The residue was purified by column chromatography over silicagel (petroleum ether/ethyl acetate 100/1 to 10/1). The desired fractionswere collected and concentrated under vacuum to give a mixture oftert-butyl-[[3-methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-naphthyl]oxy]-dimethyl-silaneandtert-butyl((3-methoxy-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)oxy)dimethylsilane(38.0 g, 85.3 mmol, 94.6% yield, 93% purity) as a light yellow oil. ESIMS m/z 415.5 [M+H]⁺

Step D: 8-[tert-butyl(dimethyl)silyl]oxy-6-methoxy

naphthalen-2-ol: To a solution of mixture (36.0 g, 86.9 mmol, 1.00 eq)oftert-butyl-[[3-methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-naphthyl]oxy]-dimethyl-silaneand tert-butyl((3-methoxy-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)oxy)dimethylsilanein in acetone (400mL) was added a solution of Oxone (58.7 g, 95.6 mmol, 1.10 eq) in H₂O(400 mL) at 0° C. The mixture was stirred at 0° C. for 1 hour. Themixture was quenched with 5% aqueous sodium thiosulfate solution (50 mL)and extracted with ethyl acetate (2×300 mL). The extracts were combinedand washed with water (1×200 mL), brine (1×200 mL), dried over magnesiumsulfate, filtered and the filtrate was concentrated under vacuum. Theresidue was purified by column chromatography over silica gel (petroleumether/ethyl acetate 200/1 to 20/1). The desired fractions were collectedand concentrated under vacuum to give8-[tert-butyl(dimethyl)silyl]oxy-6-methoxy-naphthalen-2-ol (9.00 g, 28.4mmol, 32.7% yield, 96% purity) as a colorless oil and5-[tert-butyl(dimethyl)silyl]oxy-7-methoxy-naphthalen-2-ol (9.00 g, 29.0mmol, 33.4% yield, 98% purity) as a white solid. ESI MS m/z 305.2 [M+H]⁺

Step E:[5-[tert-butyl(dimethyl)silyl]oxy-7-methoxy-2-naphthyl]trifluoromethanesulfonate

To a solution of5-[tert-butyl(dimethyl)silyl]oxy-7-methoxy-naphthalen-2-ol (11.0 g, 36.1mmol, 1.00 eq) and DIEA (14.0 g, 108 mmol, 18.9 mL, 3.00 eq) in DCM (150mL) was added Tf₂O (12.2 g, 43.4 mmol, 7.15 mL, 1.20 eq) dropwise at−40° C. The mixture was stirred for 1 hour. The mixture was diluted withdichloromethane (200 mL) and washed with water (1×200 mL) and brine(1×200 mL). The separated organic layer was dried over sodium sulfate,filtered and concentrated under vacuum. The residue was purified bycolumn chromatography over silica gel (petroleum ether/ethyl acetate100/1 to 10/1). The desired fractions were collected and concentratedunder vacuum to give[5-[tert-butyl(dimethyl)silyl]oxy-7-methoxy-2-naphthyl]trifluoromethanesulfonate (13.0 g, 29.8 mmol, 82.4% yield, 100% purity)as a white solid. ESI MS m/z 436.9 [M+H]⁺

Step F: tert-butyl-[(3-methoxy-6-methyl-1-naphthyl)oxy]-dimethyl-silane

To a solution of[5-[tert-butyl(dimethyl)silyl]oxy-7-methoxy-2-naphthyl]trifluoromethanesulfonate(12.5 g, 28.6 mmol, 1.00 eq) and K₂CO₃ (11.9 g, 85.9 mmol, 3.00 eq) indioxane (160 mL) was added Pd(PPh₃)₄ (3.31 g, 2.86 mmol, 0.10 eq) andtrimethylboroxine (14.4 g, 57.3 mmol, 16.0 mL, 2.00 eq) under nitrogenatmosphere. The reaction was heated to 100° C. for 16 hours. The mixturewas diluted with ethyl acetate (200 mL) and then washed with water(1×200 mL) and brine (1×200 mL). The separated organic layer was driedover sodium sulfate, filtered and concentrated under vacuum. The residuewas purified by column chromatography over silica gel (petroleumether/ethyl acetate 100/1 to 5/1). The desired fractions were collectedand concentrated under vacuum to givetert-butyl-[(3-methoxy-6-methyl-1-naphthyl)oxy]-dimethyl-silane (8.00 g,24.6 mmol, 85.9% yield, 93% purity) as a colorless oil as red solid. ESIMS m/z 303.2 [M+H]⁺

Step G: 3-methoxy-6-methyl-naphthalen-1-ol

To a solution of tert-butyl-[(3-methoxy-6-methyl-1-naphthyl)oxy]-dimethyl-silane (8.00 g, 26.5 mmol, 1.00 eq) in THE (100 mL) wasadded TBAF (10.4 g, 39.7 mmol, 1.50 eq) at 0° C. The mixture was stirredat 0° C. for 3 hours. The mixture was diluted with water (100 mL) andethyl acetate (200 mL). The separated organic layer was washed withbrine (1×100 mL), dried over sodium sulfate, filtered and concentratedunder vacuum. The residue was purified by column chromatography oversilica gel (petroleum ether/ethyl acetate 50/1 to 5/1). The desiredfractions were collected and concentrated under vacuum to give3-methoxy-6-methyl-naphthalen-1-ol (4.70 g, 25.0 mmol, 94.4% yield) as ared solid. ESI MS m/z 188.4 [M+H]⁺

Step H: 3-methoxy-6-methyl-1-naphthyl trifluoromethanesulfonate

To a solution of 3-methoxy-6-methyl-naphthalen-1-ol (4.70 g, 25.0 mmol,1.00 eq) and DIEA (9.68 g, 74.9 mmol, 13.1 mL, 3.00 eq) in DCM (3.00 mL)was added Tf₂O (8.45 g, 30.0 mmol, 4.94 mL, 1.20 eq) dropwise at −40° C.The mixture was stirred for 1 hour. The mixture was diluted withdichloromethane (200 mL) and washed with water (1×200 mL) and brine(1×200 mL). The separated organic layer was dried over sodium sulfate,filtered and concentrated under vacuum. The residue was purified bycolumn chromatography over silica gel (petroleum ether/ethyl acetate100/1 to 10/1). 3-methoxy-6-methyl-1-naphthyl trifluoromethanesulfonate(7.70 g, 24.0 mmol, 96.20% yield, 99.90% purity) was obtained as acolorless oil. ESTMS m/z 320.7 [M+H]⁺.

The following intermediates were prepared according to the preparationfor Intermediate 3, substitutingthe appropriate phenol for2-bromo-3-fluorophenol.

Intermediate No. Structure Name Intermediate 35

2-bromo-4-(methoxymethoxy)-1- (trifluoromethoxy)benzene Intermediate 36

2-bromo-4-(methoxymethoxy)-1- (trifluoromethyl)benzene Intermediate 37

2-bromo-1-(methoxymethoxy)-4- (trifluoromethoxy)benzene Intermediate 38

2-bromo-4-fluoro-3- (methoxymethoxy)-1- methylbenzene Intermediate 39

1-bromo-3-(methoxymethoxy)-5- (trifluoromethoxy)benzene Intermediate 40

2-bromo-1-methoxy-4- (methoxymethoxy)benzene Intermediate 41

2-bromo-1-(methoxymethoxy)-3- methylbenzene Intermediate 42

2-bromo-4-(methoxymethoxy)-1- methylbenzene Intermediate 43

1-bromo-4-(methoxymethoxy)-2- (trifluoromethoxy)benzene

Intermediate 44

2-bromo-3-fluoro-1-(methoxymethoxy)-4-methylbenzene

Step 1: 3-fluoro-4-methylphenol (1.016 g, 8.055 mmol) was placed in Cs₂(3.9 mL, 64.44 mmol) and was cooled to 0° C. Br₂ (0.4150 mL, 8.055 mmol)was added and the mixture was stirred at room temperature for 2 hrs. 10%Na₂S₂O₂ was added and the mixture was extracted with DCM. The organiclayers were combined, dried and filtered to provide2-bromo-3-fluoro-4-methylphenol (1.389 g, 6.775 mmol, 84.10% yield)which was used directly in the next step.

Step 2: 2-bromo-3-fluoro-1-(methoxymethoxy)-4-methylbenzene was preparedaccording to the procedure for Intermediate 8 using2-bromo-3-fluoro-4-methylphenol in place of 2-bromo-3-fluorophenol.

Intermediate 45

2-bromo-1-isopropoxy-4-(methoxymethoxy)benzene

Step 1: 4-isopropoxyphenol (1.00 g, 6.57 mmol) and TEA (1.83 mL, 13.1mmol) were placed in DCM (25 mL). Acetyl chloride (7.56 mL, 7.56 mmol)was added dropwise and the reaction was stirred at room temperature for2 hr. Water was added and the mixture was extracted with DCM. Theorganic layer was dried, filtered and concentrated to provide4-isopropoxyphenyl acetate (1.24 g, 6.38 mmol, 97.2% yield) which wasdirectly in the next step.

Step 2: 4-Isopropoxyphenyl acetate (1.24 g, 6.585 mmol) was placed inACN (20 mL) and N-bromosuccinimide (1.173 g, 6.590 mmol) was added. Themixture was stirred for 18 hr. Water was added and the mixture wasextracted with ether. The organic layers were combined, dried, andconcentrated to provide 3-bromo-4-isopropoxyphenyl acetate (1.584 g,5.800 mmol, 88.00% yield) which was directly in the next step.

Step 3: 3-Bromo-4-isopropoxyphenyl acetate (500 mg, 1.83 mmol) wasplaced in MeOH (7 mL). A solution of KOH (111 mg, 1.98 mmol) in water (2mL) was added to mixture and was stirred for 1 hr at room temperature.The reaction mixture was adjusted to pH 3 by the addition of 1N HCl. Themixture was extracted with DCM. The extracts were combined, dried,filtered and concentrated to provide crude 3-bromo-4-isopropoxyphenolwhich was used directly the next reaction.

Step 4: 2-Bromo-1-isopropoxy-4-(methoxymethoxy)benzene was preparedaccording to the procedure for Intermediate 8 using3-bromo-4-isopropoxyphenol in place of 2-bromo-3-fluorophenol

Intermediate 46

1-bromo-3-chloro-2-isopropyl-5-(methoxymethoxy)benzene

Step 1: 1-bromo-3-chloro-2-isopropyl-5-methoxybenzene (952 mg, 3.61mmol) was placed in DCM (3 mL) and was cooled to 0° C. BBr3 (9030 μL,9.03 mmol) was added and the reaction was stirred at 0° C. for 2 hr.Water was added and the mixture was extracted with DCM. The extractswere combined and concentrated. The resulting residue was purified bysilica gel (0-20% EtOAc in hexane) to provide3-bromo-5-chloro-4-isopropylphenol (575 mg, 2.30 mmol, 63.8% yield)

Step 2: 1-bromo-3-chloro-2-isopropyl-5-(methoxymethoxy)benzene wasprepared according to the procedure for Intermediate 8 using3-bromo-5-chloro-4-isopropylphenol in place of 2—

Intermediate 47

1-iodo-3-(methoxymethoxy)naphthalene

To a solution of 4-iodonaphthalen-2-ol (0.80 g, 3.0 mmol) in DCM (20 mL)was added N-ethyl-N-isopropylpropan-2-amine (1.1 mL, 5.9 mmol) andchloro(methoxy)methane (0.29 g, 3.6 mmol) and the reaction stirred atroom temperature for 4 hours, with additional chloro(methoxy)methane(0.15 g) being added after 2 hours. The reaction was washed with brineand concentrated in vacuo. The material was purified by chromatographyusing a gradient of 0 to 10% EtOAc/hexanes as the eluent to give1-iodo-3-(methoxymethoxy)naphthalene (0.80 g, 2.5 mmol, 86% yield).

Intermediate 48 3-benzyloxy-1-bromo-naphthalene

Step A: 2,4-dibromonaphthalen-1-amine

To a solution of Br₂ (246 g, 1.54 mol, 79.3 mL) in AcOH (750 mL) wasadded a solution of naphthalen-1-amine (101 g, 705 mmol, 99.0 mL) inAcOH (500 mL) at room temperature and the reaction stirred at 70° C. for1 hour. The reaction mixture was cooled to room temperature andfiltered. The filter cake was washed with AcOH (300 mL). The solid wasnext suspended in 20% aqueous of NaOH (1.2 L). The mixture was stirredfor 20 minutes and filtered. The solid was washed with water (1 L) anddried under vacuum to give 2,4-dibromonaphthalen-1-amine (200 g, 664mmol, 94.2% yield) as gray solid. ES+APCI MS m/z 301.9 [M+H]⁺.

Step B: 4-bromo-1-diazonio-naphthalen-2-olate

To a solution of 2,4-dibromonaphthalen-1-amine (60.0 g, 199 mmol) inAcOH (900 mL) and propionic acid (150 mL) was added NaNO₂ (16.5 g, 239mmol, 13.0 mL) portionwise at 5-8° C. over 30 minutes and the reactionmixture stirred at 5-8° C. for 30 minutes. The reaction mixture waspoured into ice-water (4000 mL), the slurry filtered and the solidwashed with water (2×50 mL) to give4-bromo-1-diazonio-naphthalen-2-olate (150 g, wet crude) which was usedcrude in the next step immediately. ¹H NMR (400 MHz, CDCl₃) δ 8.12-8.10(d, J=8.4 Hz, 1H), 7.62-7.58 (t, J=7.6 Hz, 1H), 7.41-7.37 (t, J=7.6 Hz,1H), 7.31-7.29 (d, J=8.0 Hz, 1H), 7.20 (s, 1H).

Step C: 4-bromonaphthalen-2-ol

To a solution of 4-bromo-1-diazonio-naphthalen-2-olate (100 g, 402 mmol)in EtOH (2.00 L) was added portion-wise NaBH₄ (30.4 g, 803 mmol) at13-15° C. over 1 hour and the reaction stirred at 15-18° C. for 3 hours.The reaction was filtered and concentrated to dryness. The residue wasdissolved in DCM (1000 mL) and washed with water (500 mL×2). Theorganics were dried over Na₂SO₄ and concentrated to dryness. The residuewas purified by chromatography eluting with petroleum ether/EtOAc(60/1-10/1) and material re-purified by reversed phase HPLC to give4-bromonaphthalen-2-ol (40.0 g, 139 mmol, 17.3% yield, 77.4% purity) asa gray solid. ¹H NMR (400 MHz, CDCl₃) δ 8.07-8.05 (d, J=8.0 Hz, 1H),7.60-7.58 (d, J=7.6 Hz, 1H), 7.41-7.36 (m, 3H), 7.07 (s, 1H).

Step D: 3-benzyloxy-1-bromo-naphthalene

A mixture of 4-bromonaphthalen-2-ol (30.0 g, 134 mmol), BnBr (25.3 g,148 mmol, 17.6 mL) and K₂CO₃ (55.7 g, 403 mmol) in MeCN (500 mL) washeated at 80° C. for 1 hr. The reaction mixture was filtered andconcentrated to dryness. The residue was purified by silica gel columneluting with PE/EA (100/1 to 60/1) to give3-benzyloxy-1-bromo-naphthalene (40.0 g, 128 mmol, 95% yield). ¹H NMR(400 MHz, CDCl₃) δ 8.19-8.17 (d, J=8.0 Hz, 1H), 7.75-7.32 (d, J=8.8 Hz,1H), 7.64-7.63 (d, J=2.4 Hz, 1H), 7.52-7.37 (m, 7H), 7.23-7.21 (d, J=2.0Hz, 1H), 5.2 (s, 2H).

Intermediate 49 Benzyl4-(7-(3-(benzyloxy)naphthalen-1-yl)-2-(methylsulfinyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate

Step A: tert-butyl4-hydroxy-2-methylsulfanyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate

To a solution of 1-tert-butyl 4-ethyl 3-oxopiperidine-1,4-dicarboxylate(50.0 g, 184 mmol) in MeOH (1.00 L) under nitrogen was added NaOMe (49.8g, 921 mmol) and 2-methylisothiourea (62.4 g, 331 mmol, H₂SO₄). Thereaction mixture was stirred at 25° C. for 16 hours. HCl (2 M) was addedto the reaction mixture until pH-5 and then the mixture was concentratedunder reduced pressure. The residue was suspended in 300 mL of ethylacetate and 300 mL of water. The suspension was filtered. The organicphase was washed with water (1×300 mL), brine (1×200 mL), dried overNa₂SO₄, filtered and concentrated to give tert-butyl4-hydroxy-2-methylsulfanyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate(51.0 g, 138 mmol, 75.4% yield, 81.0% purity) which was used directly inthe next reaction. ES+APCI MS m/z 298.2 [M+H]⁺.

Step B: tert-butyl2-methylsulfanyl-4-(trifluoromethylsulfonyloxy)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate

To a solution of tert-butyl4-hydroxy-2-methylsulfanyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate(51.0 g, 171 mmol) in DCM (500 mL) was added DIEA (44.3 g, 343 mmol,59.9 mL) and Tf₂O (72.6 g, 257 mmol, 42.4 mL) sequentially at 0° C.under nitrogen. The reaction mixture was warmed up to 25° C. and stirredfor 16 hours. The reaction mixture was concentrated and the residuepurified by column chromatography eluting with EtOAc/Petroleum 0→10% togive tert-butyl2-methylsulfanyl-4-(trifluoromethylsulfonyloxy)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate(46.0 g, 107 mmol, 62.4% yield). ES+APCI MS m/z 430.2 [M+H]⁺.

Step C: tert-butyl4-(4-benzyloxycarbonylpiperazin-1-yl)-2-methylsulfanyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate

To a solution of tert-butyl2-methylsulfanyl-4-(trifluoromethylsulfonyloxy)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate(46.0 g, 107 mmol in DMF (500 mL) was added DIEA (27.7 g, 214 mmol, 37.4mL) and benzyl piperazine-1-carboxylate (25.9 g, 117 mmol, 22.7 mL). Thereaction was heated to 100° C. for one hour under N₂ atmosphere. Thereaction mixture was poured into ethyl acetate (300 mL). The mixture waswashed with H₂O (300 mL×3). The organic phase was washed with brine (200mL), dried over anhydrous Na₂SO₄, concentrated in vacuo. The residue waspurified by column chromatography using 0→20% EtOAc/Petroleum as eluentto give tert-butyl4-(4-benzyloxycarbonylpiperazin-1-yl)-2-methylsulfanyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate(51.0 g, 96.9 mmol, 90.5% yield, 92.0% purity) ES+APCI MS m/z 500.3[M+H]⁺.

Step D: Benzyl4-(2-methylsulfanyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate

To a solution of tert-butyl4-(4-benzyloxycarbonylpiperazin-1-yl)-2-methylsulfanyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate(25.0 g, 50 mmol) in DCM (50 mL) was added TFA (85.6 g, 750 mmol, 55.6mL). The mixture was stirred at 25° C. for 1 hour. The reaction mixturewas concentrated under reduced pressure and the residue was dissolved in300 mL of ethyl acetate and 300 mL of water and Na₂CO₃ added until pH-8.The organic layer was washed with water (1×300 mL), brine (1×200 mL) anddried over Na₂SO₄, filtered and concentrated under reduced pressure togive benzyl4-(2-methylsulfanyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate.The product was used directly to the next step without furtherpurification. ES+APCI MS m/z 400.2 [M+H]⁺.

Step E: Benzyl4-[7-(3-benzyloxy-1-naphthyl)-2-methylsulfanyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate

A mixture of 3-benzyloxy-1-bromo-naphthalene (16.3 g, 52.1 mmol), benzyl4-(2-methylsulfanyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(16.0 g, 40.1 mmol), Cs₂CO₃ (32.6 g, 100 mmol), Pd₂(dba)₃ (5.50 g, 6.01mmol) and RuPhos (3.74 g, 8.01 mmol) in dioxane (300 mL) was degassedwith N₂ 3 times and the mixture stirred at 85° C. for 5 hour under N2atmosphere. The reaction mixture was quenched by addition water (200 mL)at 0° C., and extracted with EtOAc (3×200 mL). The combined organiclayers were washed with brine (3×150 mL), dried over Na₂SO₄, filteredand concentrated under reduced pressure. The residue was purified bycolumn chromatography eluting with 10-20% MeOH/DCM to give benzyl4-[7-(3-benzyloxy-1-naphthyl)-2-methylsulfanyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate (16.0 g, 22.8 mmol, 56.9% yield,90.0% purity ES+APCI MS m/z 632.5 [M+H]⁺.

Step F: benzyl4-[7-(3-benzyloxy-1-naphthyl)-2-methylsulfinyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate

To a solution of benzyl4-[7-(3-benzyloxy-1-naphthyl)-2-methylsulfanyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(8.00 g, 12.7 mmol) in DCM (200 mL) was added m-CPBA (2.73 g, 12.7 mmol,80.0% purity) at 0° C. under nitrogen atmosphere. The reaction mixturewas stirred for two hours under 0° C. The reaction mixture was quenchedby addition Na₂S₂O₃ (10 mL) at 0° C., and then diluted with water (100mL) and extracted with DCM (200 mL). The combined organic layers werewashed with brine (200 mL), dried over Na₂SO₄, filtered and concentratedunder reduced pressure. The residue was purified by columnchromatography eluting with 0→10% MeoH/DCM to benzyl4-[7-(3-benzyloxy-1-naphthyl)-2-methylsulfinyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(3.50 g, 4.92 mmol, 38.8% yield, 91.0% purity) ES+APCI MS m/z 648.5[M+H]⁺.

Intermediate 50 Tert-butyl4-(4-benzyloxycarbonylpiperazin-1-yl)-2-methylsulfonyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate

Step A: tert-butyl4-(4-benzyloxycarbonylpiperazin-1-yl)-2-methylsulfonyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate

To a stirred solution oftert-butyl4-(4-benzyloxycarbonylpiperazin-1-yl)-2-methylsulfanyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate(14.4 g, 28.9 mmol) in DCM (150 mL) was added m-CPBA solid (17.4 g, 101mmol) at 0° C. under nitrogen. After stirring at 0° C. for 2 hours, thereaction mixture was diluted with water (300 mL) and basified withsaturated NaHCO₃ aqueous solution to pH 8 and then extracted with DCM(3×200 mL). The combined organic layers were washed with brine (3×200mL), dried over Na₂SO₄, filtered and concentrated under reducedpressure. The residue was purified by column chromatography (SiO₂,Petroleum ether/Ethyl acetate 10/1 to 1/2) to give tert-butyl4-(4-benzyloxycarbonylpiperazin-1-yl)-2-methylsulfonyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate(11.0 g, 19.7 mmol, 68.6% yield, 95.4% purity). ES+APCI MS m/z 532.1[M+H]⁺.

Intermediate 51 4-bromo-5-methyl-1-tetrahydropyran-2-yl-indazole

Step A: 4-bromo-5-methyl-1-tetrahydropyran-2-yl-indazole

To a mixture of 4-bromo-5-methyl-1H-indazole (3 g, 14.2 mmol) and3,4-dihydro-2H-pyran (2.39 g, 28.4 mmol, 2.60 mL) in DCM (30 mL) wasadded TsOH*H₂O (270 mg, 1.42 mmol) and the mixture stirred at 15° C. for2 hours. After completion, the reaction mixture was concentrated undervacuum and the residue purified by column chromatography using 5→20&EtOAc/Petroleum Ether as eluent to give4-bromo-5-methyl-1-tetrahydropyran-2-yl-indazole (4 g, 13.6 mmol, 95.3%yield) as white solid. ¹H NMR (400 MHz, chloroform-d) δ 8.01 (s, 1H),7.47 (d, J=8.4 Hz, 1H), 7.25 (d, J=8.4 Hz, 1H), 5.70 (dd, J=2.8, 9.2 Hz,1H), 4.05-3.96 (m, 1H), 3.79-3.70 (m, 1H), 2.66-2.44 (m, 4H), 2.25-2.04(m, 2H), 1.84-1.56 (m, 3H).

Intermediate 524-bromo-5-methoxy-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole

4-bromo-5-methoxy-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole was preparedfollowing Intermediate 51 substituting 4-bromo-5-methoxy-1H-indazole for4-bromo-5-methyl-1H-indazole in Step A. 1H NMR (400 MHz, chloroform-d) δ8.00 (s, 1H), 7.53 (d, J=9.2 Hz, 1H), 7.16 (d, J=9.2 Hz, 1H), 5.70 (dd,J=2.8, 9.2 Hz, 1H), 4.04-3.98 (m, 1H), 3.96 (s, 3H), 2.55-2.49 (m, 1H),2.23-2.05 (m, 2H), 1.83-1.69 (m, 3H).

Intermediate 53 3-(benzyloxy)-1-bromo-2-methylnaphthalene

Step A: Ethyl 2-methyl-3-oxo-4-phenyl-butanoate

To a dried 250 ml three-necked flask was added ethyl3-oxo-4-phenyl-butanoate (4.00 g, 19.4 mmol.), THE (50.0 mL), sodiumhydride (931 mg, 23.3 mmol) and the reaction stirred for 0.5 hours at 0°C. A solution of methyl iodide (3.03 g, 21.3) was next added drop-wise.After addition was completed, the reaction mixture was warmed to 20° C.and stirred for two hours at 20° C. The reaction mixture was quenched byaddition of water (10.0 mL) at 20° C. and then diluted with ethylacetate (20.0 mL) and the layers separated. The aqueous layer was nextextracted with ethyl acetate (20.0 mL×3). The combined organic layerswere washed with brine (30.0 mL), dried over anhydrous sodium sulfate,filtered and concentrated under reduced pressure to give a residue. Theresidue was purified by column chromatography (SiO2, Petroleum ether:Ethyl acetate 20:1 to 10:1) to give ethyl2-methyl-3-oxo-4-phenyl-butanoate (3.60 g, 16.3 mmol, 84.3% yield) as acolorless oil. ¹H NMR (400 MHz, CDCl₃) δ=7.38-7.28 (m, 3H), 7.25-7.19(m, 2H), 4.22-4.15 (m, 2H), 3.87 (d, J=2.0 Hz, 2H), 3.65 (q, J=7.2 Hz,1H), 1.34 (d, J=7.2 Hz, 3H), 1.30-1.26 (m, 3H).

Step B: 2-methylnaphthalene-1,3-diol

A solution of ethyl 2-methyl-3-oxo-4-phenyl-butanoate (3.60 g, 16.3mmol) in concentrated sulfuric acid (19.9 g, 203 mmol) was stirred at15° C. for 12 hours. The reaction mixture was poured into ice-water(30.0 mL) and the resulting solid collected by filtration and driedunder vacuum to afford 2-methylnaphthalene-1,3-diol (1.80 g, 10.3 mmol,63.2% yield) as a red solid. ¹H NMR (400 MHz, CDCl₃) δ=8.02 (d, J=8.0Hz, 1H), 7.65-7.54 (m, 1H), 7.41 (t, J=7.2 Hz, 1H), 7.36-7.31 (m, 1H),6.80 (s, 1H), 4.29-4.20 (s, 2H), 2.41-2.24 (s, 3H).

Step C: 3-methoxy-2-methyl-naphthalen-1-ol

2-methylnaphthalene-1,3-diol (1.70 g, 9.76 mmol) was added to HCl/MeOH(2 M, 35.0 mL) and the result mixture was stirred at 30° C. for 3 days.The reaction was concentrated in vacuo and the residue purified byPrep-TLC (Petroleum ether: Ethyl acetate 1:1) to give3-methoxy-2-methyl-naphthalen-1-ol (800 mg, 4.25 mmol, 43.5% yield) as awhite solid. ¹H NMR (400 MHz, CDCl₃) δ=8.02 (d, J=8.4 Hz, 1H), 7.69 (d,J=8.4 Hz, 1H), 7.44-7.38 (m, 1H), 7.37-7.31 (m, 1H), 6.79 (s, 1H), 5.14(s, 1H), 3.94 (s, 3H), 2.29 (s, 3H).

Step D: (3-methoxy-2-methyl-1-naphthyl)trifluoromethanesulfonate

To a mixture of 3-methoxy-2-methyl-naphthalen-1-ol (800 mg, 4.25 mmol.)and pyridine (504 mg, 6.38 mmol) in DCM (10.0 mL) was addedtrifluoroacetic anhydride (1.44 g, 5.10 mmol) dropwise at 0° C. under N₂atmosphere. The mixture was warmed to 20° C. and stirred for anadditional 5 hours. The solvent was removed under vacuum and the residuepurified by Prep-TLC (Petroleum ether:Ethyl acetate 1:1) to give(3-methoxy-2-methyl-1-naphthyl)trifluoromethanesulfonate (1.30 g, 4.06mmol, 95.5% yield) as a white solid. ¹H NMR (400 MHz, CDCl₃) δ=7.97 (d,J=7.6 Hz, 1H), 7.79-7.74 (m, 1H), 7.52-7.43 (m, 2H), 7.14 (s, 1H), 3.99(s, 3H), 2.42 (s, 3H)

Step E: 1-bromo-3-methoxy-2-methyl-naphthalene

In a sealed tube was added(3-methoxy-2-methyl-1-naphthyl)trifluoromethanesulfonate (466 mg, 1.45mmol), t-Bu-Brettphos (154 mg, 290 umol), potassium bromide (259 mg,2.17 mmol), PEG-200 (175 mg), 2-butanone (157 mg, 2.17 mmol) andPd₂(dba)₃ (133 mg, 145 umol) in toluene (10.0 mL) and the mixturede-gassed with N2 for 5 minutes. Next, triisobutylaluminum (431 mg, 2.17mmol) was added drop-wise at 20° C. The mixture was heated to 100° C.for 24 hrs. The reaction mixture was poured into water (30.0 mL) and theaqueous layer extracted with ethyl acetate (20.0 mL×3). The combinedorganics were washed with brine (30.0 mL), dried over anhydrous sodiumsulfate and concentrated in vacuo to give a residue which waspre-purified by column chromatography (Petroleum ether:Ethyl acetate10:1) and then by Prep-TLC (Petroleum ether:Ethyl acetate 10:1) to give1-bromo-3-methoxy-2-methyl-naphthalene (700 mg, 2.79 mmol, 64.1% yield)as a white solid. ¹H NMR (400 MHz, CDCl₃) δ=8.26-8.17 (m, 1H), 7.73-7.69(m, 1H), 7.47-7.40 (m, 2H), 7.09 (s, 1H), 3.98-3.95 (m, 3H), 2.56 (s,3H).

Step F: 4-bromo-3-methyl-naphthalen-2-ol

To a solution of 1-bromo-3-methoxy-2-methyl-naphthalene (580 mg, 2.31mmol) and tetrabutylammonium iodide (2.13 g, 5.78 mmol) in DCM (11.0 mL)cooled to −78° C. was added a solution of BC13 (1 M, 5.78 mL) dropwiseover a period of 10 minutes while under N₂. The reaction mixture waswarmed to 0° C. and stirred for 2 hours at room temperature. Next thesolvent was removed under vacuum and the residue was purified byPrep-TLC (Petroleum ether:Ethyl acetate 5:1) to give4-bromo-3-methyl-naphthalen-2-ol (500 mg, 2.11 mmol, 91.3% yield) as awhite solid. ¹H NMR (400 MHz, CDCl₃) δ=8.26-8.15 (m, 1H), 7.63 (dd,J=3.6, 6.0 Hz, 1H), 7.45-7.38 (m, 2H), 7.11 (s, 1H), 5.09 (s, 1H), 2.60(s, 3H), 1.56 (s, 3H).

Step G: 3-benzyloxy-1-bromo-2-methyl-naphthalene

To a mixture of 4-bromo-3-methyl-naphthalen-2-ol (265 mg, 1.12 mmol) andbenzyl bromide (201 mg, 1.18 mmol) in acetonitrile (3.00 mL) was addedpotassium carbonate (310 mg, 2.24 mmol) in one portion at 20° C. underN₂. The mixture was next stirred at 60° C. for two hours. The solventwas removed under vacuum and the residue purified by Prep-TLC (Petroleumether:Ethyl acetate 5:1) to give the3-benzyloxy-1-bromo-2-methyl-naphthalene (250 mg, 695 umol, 31.0% yield,91.0% purity) as a white solid. ES+APCI MS m/z 327.0, 329.0 [M+H]⁺.

Intermediate 54tert-butyl-2-(cyanomethyl)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate

Step A: (4-bromo-2-naphthyl) 2,2-dimethylpropanoate

To a solution of 4-bromonaphthalen-2-ol (10 g, 44.8 mmol) and TEA (9.07g, 89.7 mmol) in DCM (200 mL) was added 2,2-dimethylpropanoyl chloride(8.11 g, 67.2 mmol) at 0° C. The reaction mixture was stirred at 0° C.for 10 min. T reaction mixture was quenched by addition of water (50 mL)and the layers separated. The organic layer was washed with brine (30mL), dried over Na₂SO₄ filtered and concentrated under vacuum. Theresidue was purified by silica gel chromatography (PE:EA=1:0 to 100:1)to give (4-bromo-2-naphthyl) 2,2-dimethylpropanoate (9 g, 29.3 mmol,65.4% yield) as a red oil. ¹H NMR (400 MHz, CHLOROFORM-d) δ=8.22 (d,J=8.0 Hz, 1H), 7.83-7.77 (m, 1H), 7.63-7.49 (m, 4H), 1.41 (s, 9H).

Intermediate 55 Tert-butyl4-(2-(3-morpholinopropoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate

Step A: 7-benzyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-2,4-diol

To EtOH (600 mL) was added Na (5.56 g, 241 mmol) in portions and themixture stirred for 1 hour. To this solution was added ethyl1-benzyl-3-oxo-piperidine-4-carboxylate (30.0 g, 100 mmol) and urea(14.5 g, 242 mmol) and the reaction mixture stirred at 75° C. for 36hours. The solvent was removed under vacuum and the residue dissolved inwater (50 mL) and acidified by addition of HCl (120 mL, 2M) at whichpoint a solid precipitated. The solid was filtered and the filter cakedried under vacuum to give7-benzyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-2,4-diol (22.0 g, 83.8mmol). ¹HNMR (400 MHz, DMSO-d₆) δ=10.97 (br s, 1H), 10.66 (br s, 1H),7.55-6.95 (m, 5H), 3.81-3.50 (m, 2H), 3.26-2.91 (m, 2H), 2.77-2.58 (m,2H), 2.34-2.09 (m, 2H).

Step B: 7-benzyl-2,4-dichloro-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine

To a solution of DIEA (30.1 g, 233 mmol) in POCl₃ (330 g, 2.15 mol) wasadded 7-benzyl-6,8-dihydro-5H-pyrido[3,4-d] pyrimidine-2,4-diol (20.0 g,77.7 mmol) and the reaction mixture stirred at 110° C. for 5 hours. Uponcompletion, the reaction mixture was concentrated under vacuum. Theresidue was dissolved in DCM (400 mL) and poured into sat. NaHCO₃ (200mL) and the layers separated. The aqueous layer was extracted with DCM(2×400 mL). The combined organics were washed with brine (100 mL), driedover Na₂SO₄ and concentrated under vacuum. The residue was purified bysilica gel chromatography (PE/DCM=10/1 to 0/1) to give7-benzyl-2,4-dichloro-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine (7.70 g,26.2 mmol). ¹HNMR (300 MHz, chloroform-d) 6=7.43-7.28 (m, 5H), 3.73 (s,2H), 3.66 (br s, 2H), 2.84 (br s, 4H).

Step C: tert-butyl4-(7-benzyl-2-chloro-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate

To a solution of7-benzyl-2,4-dichloro-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine (17.3 g,58.8 mmol) in DMSO (200 mL) was added DIEA (19.0 g, 147 mmol) andtert-butyl piperazine-1-carboxylate (11.5 g, 61.7 mmol) and the mixturestirred at 55° C. for 10 hours. The reaction mixture was poured intoethyl acetate (200 mL) and washed with water (3×200 mL). The combinedorganics were washed with brine (200 mL), dried over anhydrous Na₂SO₄and concentrated under vacuum to give a residue. The residue waspurified by trituration from MTBE (200 mL) to give tert-butyl4-(7-benzyl-2-chloro-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate (24 g, 52.9 mmol). ES+APCI MS m/z 444.2 [M+H]⁺.

Step D: tert-Butyl4-[7-benzyl-2-(3-morpholinopropoxy)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate

A mixture of 3-morpholinopropan-1-ol (11.8 g, 81.1 mmol), tert-butyl4-(7-benzyl-2-chloro-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(18 g, 40.5 mmol), BINAP (5.05 g, 8.11 mmol), t-BuONa (9.74 g, 101 mmol)and Pd₂(dba)₃ (3.71 g, 4.05 mmol) in toluene (300 mL) was degassed andpurged with N₂ 3 times, and the mixture stirred at 110° C. for 3 hoursunder N₂ atmosphere. The reaction mixture was poured into H₂O (200 mL)and the aqueous layer extracted with ethyl acetate (3×300 mL). Thecombined organics were washed with brine (200 mL), dried over anhydrousNa₂SO₄ and concentrated under vacuum to give a residue. The residue waspurified by column chromatography (SiO₂, Petroleum ether/Ethylacetate=100/1 to 5/1) to give tert-Butyl4-[7-benzyl-2-(3-morpholinopropoxy)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(14 g, 22.5 mmol). ES+APCI MS m/z 553.4 [M+H]⁺.

Step E: tert-butyl4-[2-(3-morpholinopropoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate

To a solution of tert-butyl4-[7-benzyl-2-(3-morpholinopropoxy)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(14 g, 25.3 mmol) in MeOH (1 L) was added dry Pd/C (3 g, 10% purity)under N₂. The suspension was degassed under vacuum and purged with H₂several times. The mixture was stirred under H₂ (15 psi) at 40° C. for10 hours. The mixture was filtered and the filtrate concentrated invacuo to give a residue. The residue was purified by reversed phaseflash [water (0.1 TFA)/acetonitrile] to give tert-butyl4-[2-(3-morpholinopropoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate (6.5 g, 13.9 mmol). ES+APCI MS m/z 463.4[M+H]⁺.

Intermediate 56

Naphthalen-1-yl Trifluoromethanesulfonate

alpha-Naphthol (4 g, 27.74 mmol) was dissolved in DCM (200 mL) in a 3neck flask. The reaction was cooled to 10° C. in a water bath.N-ethyl-N-isopropylpropan-2-amine (4.846 ml, 27.74 mmol) andtrifluoromethanesulfonic anhydride (4.668 ml, 27.74 mmol) were added tothe solution dropwise. The reaction was stirred at 10° C. for 2 hours.TLC (25% EtOAc, UV vis) showed reaction complete. The organics were withwater (2×) and brine (2×). The organics were dried over MgSO4 andconcentrated in vacuo. The concentrate was purified using normal phasechromatography on the CombiFlash (0%-12% EtOAc:Hexanes). All fractionscontaining clean product were combined and concentrated in vacuo to givenaphthalen-1-yl trifluoromethanesulfonate (6.77 g, 24.51 mmol, 88.34%yield).

Intermediate 57

Tert-butyl(S)-2-(hydroxymethyl)-4-methylpiperazine-1-carboxylate

To a solution of (S)-1-Boc-2-hydroxymethylpiperazine (1.0 g, 4.62 mmol)in DCE (92.47 ml, 4.624 mmol) was added formaldehyde (3.474 ml, 46.24mmol) (37% in water) followed by sodium triacetoxyborohydride (4.9 g,23.12 mmol). The mixture was stirred vigorously at room temperature for2.5 hours. The mixture was treated with saturated sodium bicarbonate (30mL), stirred for 10 min then extracted with DCM (3×10 mL). The combinedorganic phases were dried over sodium sulfate, filtered andconcentrated. ES+APCI MS m/z 231.1 [M+H]⁺.

Intermediate 58

Tert-butyl (R)-2-(hydroxymethyl)-4-methylpiperazine-1-carboxylate

Title compound was prepared as in Intermediate 57, substitutingtert-butyl (R)-2-(hydroxymethyl)piperazine-1-carboxylate for(S)-1-Boc-2-hydroxymethylpiperazine. ES+APCI MS m/z 231.1 [M+H]⁺

Intermediate 59

1-bromo-3-chloro-2-fluoro-5-(methoxymethoxy)benzene

To a round bottom flask was added THE (8.87 ml, 4.44 mmol) followed bysodium hydride, 60% dispersion in mineral oil (0.213 g, 5.32 mmol). Themixture was cooled to 0° C. then 3-bromo-5-chloro-4-fluorophenol (1.0 g,4.44 mmol) was added portionwise. Once the bubbling had ceased theresulting dark mixture was stirred at 0° C. for 30 min. Thenchloromethyl methyl ether (0.421 ml, 5.54 mmol) was added and themixture was warmed to ambient temperature where it was stirred for 2 hr.A saturated aqueous ammonium chloride solution was added and the mixturewas extracted with DCM. The organic layer was dried over sodium sulfate,filtered and concentrated. Crude material was chromatographed (0-15%EtOAc in hexanes) to provide product as clear oil.

Intermediate 604-bromo-1-tetrahydropyran-2-yl-5-(trifluoromethyl)indazole

Step A: 4-bromo-1-tetrahydropyran-2-yl-5-(trifluoromethyl)indazole

To a solution of 4-bromo-5-(trifluoromethyl)-1H-indazole (500 mg, 1.89mmol, 1 eq) in DCM (10 mL) was added 3,4-dihydro-2H-pyran (476 mg, 5.66mmol, 517 uL, 3 eq) and TsOH H₂O (35.9 mg, 188 umol, 0.1 eq). Themixture was stirred at 15° C. for 1 hour. The mixture was concentrated.The residue was purified by column chromatography (SiO₂, PE:EA=10:1 to1:1) to give 4-bromo-1-tetrahydropyran-2-yl-5-(trifluoromethyl)indazole(480 mg, 1.37 mmol, 72.9% yield) as yellow oil. ¹H NMR (400 MHz,chloroform-d) δ 8.20 (s, 1H), 7.69-7.63 (m, 2H), 5.70 (dd, J=2.8, 8.8Hz, 1H), 4.05-3.96 (m, 1H), 3.79-3.70 (m, 1H), 2.56-2.50 (m, 1H),2.27-2.04 (m, 2H), 1.80-1.74 (m, 2H), 1.60-1.54 (m, 1H).

Intermediate 61

8-bromo-6-(methoxymethoxy)quinoline

A stirred suspension of 8-bromoquinolin-6-ol (1.00 g, 4.46 mmol) in DCM(20 mL) was cooled to 0° C. and diisopropylethylamine (1.2 mL, 6.7 mmol,1.5 eq.) was added followed by chloro(methoxy)methane (0.41 mL, 5.4mmol, 1.2 eq.) dropwise and the reaction mixture was warmed to roomtemperature overnight. Concentrated aqueous ammonia (0.5 mL, −5 mmol)was next added and the resulted mixture was stirred for 1 hour at roomtemperature. The mixture was evaporated in vacuo and chromatographed onsilica gel, Redisep 40 g, using 20% EtOAc/hexane as eluent to give acolorless powder (0.52 g, 44%). ES+APCI MS m/z 268.0, [M+H]⁺.

Example 1

1-(4-(7-(3-hydroxynaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Step A: tert-butyl4-(4-((benzyloxy)carbonyl)piperazin-1-yl)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate

In 2 mL of dimethyl acetamide were combined tert-butyl4-chloro-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate (1.0 g,3.7 mmol), triethylamine (1.0 mL, 7.4 mmol), and benzyl1-piperazinecarboxylate (0.86 mL, 4.4 mmol). The reaction vessel wassealed and the reaction mixture was heated to 90° C. with stirring.After 5 hours, the reaction was diluted with brine and extracted withmethyl t-butyl ether. The combined organic layers were washedsequentially with saturated ammonium chloride and brine, dried overMgSO4, and concentrated under reduced pressure to a thick oil. The oilwas chromatographed (RediSep®, 24 g) eluting with 1:1 ethylacetate/Hexanes to give tert-butyl4-(4-((benzyloxy)carbonyl)piperazin-1-yl)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate(1.3 g, 2.9 mmol, 77% yield). ES+APCI MS m/z 454.2 [M+H]⁺.

Step B: Benzyl4-(5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate

To a solution of tert-butyl4-(4-((benzyloxy)carbonyl)piperazin-1-yl)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate(1.58 g, 3.484 mmol) in dichloromethane (11.61 mL, 3.484 mmol) was addedtrifluoroacetic acid (2.668 mL, 34.84 mmol) and the reaction was stirredat room temperature for 3 hours. The reaction was concentrated undervacuum and the residue was taken up in dichloromethane. The solution waswashed with sequentially with 1M NaOH and brine, dried over Na₂SO₄,filtered and concentrated under vacuum. The crude product was purifiedby column chromatography (Biotage Isolera, 24G Isco RediSep® Gold, 10 to20% methanol/dichloromethane) to afford the product (1.1 g, 89%) as anoff-white foam. ES+APCI MS m/z 354.2 [M+H]⁺.

Step C: benzyl4-(7-(3-(methoxymethoxy)naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate

To a vial was added tris(dibenzylideneacetone)dipalladium (0) (0.0069 g,0.0075 mmol), racemic-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl(0.0096 g, 0.015 mmol) and toluene (0.62 mL, 0.19 mmol). Argon wasbubbled through the mixture for 5 minutes and then the vial was cappedand the mixture was heated to 100° C. for 15 minutes. The mixture wascooled to ambient temperature and then sodium tert-butoxide (0.036 g,0.37 mmol) was added followed by 1-bromo-3-(methoxymethoxy)naphthalene(0.050 g, 0.19 mmol) and benzyl4-(5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(0.13 g, 0.37 mmol). The vial was capped and the mixture heated to 100°C. for 20 hours. The mixture was cooled to ambient temperature, dilutedwith dichloromethane and filtered through GF/F paper. The filtrate wasconcentrated and purified by column chromatography (Biotage Isolera, 12GIsco RediSep®, 10-50% ethyl acetate/dichloromethane) to afford theproduct (0.062 g, 61%) as an off-white foam. ES+APCI MS m/z 540.3[M+H]⁺.

Step D:7-(3-(methoxymethoxy)naphthalen-1-yl)-4-(piperazin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine

To a solution of benzyl4-(7-(3-(methoxymethoxy)naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(0.061 g, 0.11 mmol) in ethanol (1.1 mL, 0.11 mmol) and tetrahydrofuran(1.1 mL, 0.11 mmol) was added palladium (0.024 g, 0.011 mmol) (DegussaType, 10 wt. %, 50% H₂O). An atmosphere of H₂ was introduced into thereaction vessel by vacuum, and then the reaction mixture was maintainedunder an atmosphere of H₂. The mixture was stirred at ambienttemperature for 2.5 hours, then diluted with methanol and filteredthrough GF/F paper. The colorless filtrate was concentrated under vacuumwith toluene to provide an off-white foam (0.048 g, 105%) that was useddirectly in the next step. ES+APCI MS m/z 406.2 [M+H]⁺.

Step E:1-(4-(7-(3-(methoxmethox)naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

To a suspension of7-(3-(methoxymethoxy)naphthalen-1-yl)-4-(piperazin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine(0.046 g, 0.11 mmol) in dichloromethane (1.1 mL, 0.11 mmol) at ambienttemperature was added acryloyl chloride (1.2 mL, 0.12 mmol) (freshlyprepared 0.1 M solution in dichloromethane) followed by triethylamine(0.032 mL, 0.23 mmol). The reaction was stirred at ambient temperaturefor 1 hour. The mixture was concentrated and the product was purified bycolumn chromatography (Biotage Isolera, 12G Isco RediSep®, ethylacetate) to afford the product (0.042 g, 79%) as an off-white solidfoam. ES+APCI MS m/z 460.2 [M+H]⁺.

Step F:1-(4-(7-(3-hydroxynaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

To a solution of1-(4-(7-(3-(methoxymethoxy)naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one(0.034 g, 0.074 mmol) in ethyl acetate (0.74 mL, 0.074 mmol) was addedhydrochloric acid (5 to 6 N solution in 2-propanol (0.44 mL, 2.2 mmol).The mixture was stirred at ambient temperature for 5 hours. The mixturewas diluted with ethyl acetate (10 mL), filtered through a polypropylenefilter and the collected solid was washed with ethyl acetate and hexanesto provide the product as the HCl salt. The impure material was treatedwith 1 mL of ammonium hydroxide/methanol to quench the acid and themixture was concentrated. The residue was dissolved in 10%methanol/dichloromethane and purified by column chromatography (BiotageIsolera, 12G Isco RediSep®, 2 to 5% methanol/ethyl acetate) to affordthe product (0.008 g, 25%) as an off-white solid. ES+APCI MS m/z 416.2[M+H]⁺.

1H NMR (CD3OD, 400 MHz) δ 8.49 (s, 1H), 8.07 (app d, J=8.2 Hz, 1H), 7.61(app d, J=8.2 Hz, 1H), 7.35 (m, 1H), 7.25 (m, 1H), 6.80 (m, 3H), 6.23(dd, J=16.8, 1.6 Hz, 1H), 5.77 (dd, J=10.6, 2.0 Hz, 1H), 4.22 (br s,2H), 3.80 (app t, J=4.7 Hz, 4H), 3.63 (br s, 4H), 3.35 (br s, 2H), 3.03(br s, 2H).

Example 2

1-(4-(7-(7-hydroxynaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Synthesized according to the method of Example 1, using2-bromo-7-(methoxymethoxy)naphthalene in place of1-bromo-3-(methoxymethoxy)naphthalene in Step C. ES+APCI MS m/z 416.1[M+H]⁺.

Example 3

1-(4-(7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Synthesized according to the method of Example 1, using1-iodonaphthalene in place of 1-bromo-3-(methoxymethoxy)naphthalene inStep C. ES+APCI MS m/z 400.2 [M+H]⁺.

Example 4

1-(4-(7-(2-fluoro-6-hydroxyphenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Synthesized according to the method of Example 1, using2-bromo-1-fluoro-3-(methoxymethyl)benzene in place of1-bromo-3-(methoxymethoxy)naphthalene in Step C. ES+APCI MS m/z 384.2[M+H]⁺.

Example 5

1-(4-(7-(2-fluoro-5-hydroxyphenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Synthesized according to the method of Example 1, using2-bromo-1-fluoro-4-(methoxymethoxy)benzene in place of1-bromo-3-(methoxymethoxy)naphthalene in Step C. ES+APCI MS m/z 384.2[M+H]⁺.

Example 6

1-(4-(7-(3-hydroxynaphthalen-1-yl)-6-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-oneSteps A-C: Benzyl4-(7-(3-(methoxymethoxy)naphthalen-1-yl)-6-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate

Synthesized according to the method of Example 1, Steps A-C, usingtert-butyl4-chloro-6-methyl-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylatein place of4-chloro-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate in Step A.ES+APCI MS m/z 430.2 [M+H]⁺.

Step D1: benzyl4-(7-(3-hydroxynaphthalen-1-yl)-6-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate

To a solution of benzyl4-(7-(3-(methoxymethoxy)naphthalen-1-yl)-6-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(0.05 g, 0.09 mmol) in isopropanol (10 mL) was added hydrogen chloride(5-6M in isopropanol) (0.02 mL, 0.09 mmol) and the reaction stirred atroom temperature for 1 hour. The reaction was concentrated under vacuumand the concentrate was partitioned between ethyl acetate and water toconvert the material to the free base. The combined organic layers werewashed with brine, dried over MgSO4 and concentrated under vacuum togive benzyl4-(7-(3-hydroxynaphthalen-1-yl)-6-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(0.005 g, 0.010 mmol, 11% yield). ES+APCI MS m/z 510.3 [M+H]⁺.

Step D2:4-(7-(3-hydroxynaphthalen-1-yl)-6-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-ol

Prepared according to the method of Example 1, Step D.

Step E:1-(4-(7-(3-hydroxynaphthalen-1-yl)-6-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Prepared according to the method of Example 1, Step E.

Example 7

1-(4-(7-(5-methyl-1H-indazol-4-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Steps A-D: benzyl4-(7-(5-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-4-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate:Synthesized according to General Scheme 1, Steps A-C, using4-bromo-5-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole inplace of 1-bromo-3-(methoxymethoxy)naphthalene in Step C

Step D1: benzyl4-(7-(5-methyl-1H-indazol-4-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate

To a solution of benzyl4-(7-(5-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-4-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(0.16 g, 0.26 mmol) in dichloromethane (10 mL) was added2,2,2-trifluoroacetic acid (0.89 g, 7.8 mmol) followed by anisole (0.028g, 0.26 mmol), and the reaction was stirred at room temperature for 3hours at room temperature. The reaction was concentrated under vacuumand the concentrated material was taken up in ethyl acetate and washedwith basic brine. The combined organic layers were dried over MgSO4 andconcentrated under vacuum. The crude material was chromatographed using0 to 10% methanol/dichloromethane as the eluent to give benzyl4-(7-(5-methyl-H-indazol-4-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(0.05 g, 38%). ES+APCI MS m/z 484.2 [M+H]⁺.

Step D2:7-(5-methyl-1H-indazol-4-yl)-4-(piperazin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine

Prepared according to the method of Example 1, Step D.

Step E:1-(4-(7-(5-methyl-1H-indazol-4-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Prepared according to the method of Example 1, Step E.

Example 8

(S)-1-(4-(2-((1-(dimethylamino)propan-2-yl)oxy)-7-(3-hydroxynaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Step A: tert-butyl4-(4-((benzyloxy)carbonyl)piperazin-1-yl)-2-chloro-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate

Benzyl 1-piperazinecarboxylate (1.268 mL, 6.575 mmol) and tert-Butyl2,4-dichloro-5,6-dihydropyrido[3 4-d]pyrimidine-7(8H)-carboxylate (2 g,6.575 mmol) were dissolved in dimethyl acetamide (10 mL) and treatedwith N-ethyl-N-isopropylpropan-2-amine (3.445 mL, 19.73 mmol). Thereaction mixture was stirred at 85° C. for 2 hours. The reaction mixturewas cooled to room temperature, diluted with ethyl acetate, washed withwater and brine, dried over MgSO4, filtered and concentrated. Theconcentrate was purified by chromatography (CombiFlash®, 0%-50% ethylacetate:Hexanes as the eluent to provide the product (2.69 g, 83%).ES+APCI MS m/z 488.2, 490.2 [M+H]⁺.

Step B: tert-butyl(S)-4-(4-((benzyloxy)carbonyl)piperazin-1-yl)-2-((1-(dimethylamino)propan-2-yl)oxy)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate

Tert-butyl4-(4-((benzyloxy)carbonyl)piperazin-1-yl)-2-chloro-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate(235 mg, 0.482 mmol), and (S)-1-(dimethylamino)propan-2-ol (497 mg, 4.82mmol) were added to dioxane (0.5 mL) and heated to 100° C. for 3 days.The reaction was concentrated and the resulting residue was purified bysilica gel (Biotage Isolera, 0-12% methanol in dichloromethane) toprovide tert-butyl(S)-4-(4-((benzyloxy)carbonyl)piperazin-1-yl)-2-((1-(dimethylamino)propan-2-yl)oxy)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate(200 mg, 0.361 mmol, 74.9% yield). ES+APCIMS m/z 555.3 [M+H]⁺.

Step C: benzyl(S)-4-(2-((1-(dimethylamino)propan-2-yl)oxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate

To a solution of tert-butyl(S)-4-(4-((benzyloxy)carbonyl)piperazin-1-yl)-2-((1-(dimethylamino)propan-2-yl)oxy)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate(200 mg, 0.3606 mmol) in dichloromethane (1202 μL, 0.3606 mmol) wasadded trifluoroacetic acid (828.3 μL, 10.82 mmol) and the reaction wasstirred at room temperature for 3 hours. The reaction was concentratedunder vacuum and the residue was taken up in dichloromethane. Thesolution was washed with 1M NaOH followed by brine and then dried overNa₂SO₄, filtered and concentrated under vacuum. The crude product waspurified by column chromatography (Biotage Isolera, 24G IscoRediSep®Gold, 10 to 20% methanol/dichloromethane) to afford the productas an off-white foam (0.135 g, 83%). ES+APCI MS m/z 455.2 [M+H]⁺.

Step D: benzyl(S)-4-(2-((1-(dimethylamino)propan-2-yl)oxy)-7-(3-(methoxymethoxy)naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate

To a vial was added tris(dibenzylideneacetone)dipalladium (0) (21.8 mg,0.0238 mmol), racemic-2,2′-Bis(diphenylphosphino)-1,1′-binaphthyl (30.4mg, 0.0488 mmol) and toluene (991 μL, 0.297 mmol). Argon was bubbledthrough the mixture for 5 minutes and then the vial was capped and themixture was heated to 100° C. for 15 minutes. The mixture was cooled toambient temperature and sodium tert-butoxide (57.2 mg, 0.595 mmol) wasadded followed by 3-(methoxymethoxy)naphthalen-1-yltrifluoromethanesulfonate (100 mg, 0.297 mmol) and benzyl(S)-4-(2-((1-(dimethylamino)propan-2-yl)oxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(135 mg, 0.297 mmol). The vial was capped and the mixture was heated to100° C. for 18 hours. The mixture was cooled and concentrated. The crudematerial was purified by silica gel (Biotage Isolera, 0-11%methanol/dichloromethane to provide benzyl(S)-4-(2-((1-(dimethylamino)propan-2-yl)oxy)-7-(3-(methoxymethoxy)naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(68 mg, 0.106 mmol, 35.7% yield). ES+APCI MS m/z 641.3 [M+H]⁺.

Step E:(S)-2-((7-(3-(methoxymethoxy)naphthalen-1-yl)-4-(piperazin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)oxy)-N,N-dimethylpropan-1-amine

To a solution of benzyl(S)-4-(2-((1-(dimethylamino)propan-2-yl)oxy)-7-(3-(methoxymethoxy)naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(68 mg, 0.11 mmol) in ethanol (1061 μL, 0.11 mmol) and tetrahydrofuran(1061 μL, 0.11 mmol) was added Palladium (113 mg, 0.053 mmol) (DegussaType, 10 wt. %, 50% H₂O). An atmosphere of H₂ was introduced by vacuumand then the reaction vessel was maintained under an atmosphere of H₂.The mixture was stirred at ambient temperature for 3 hours. The mixturewas diluted with methanol and filtered through GF/F paper. The colorlessfiltrate was concentrated to provide(S)-2-((7-(3-(methoxymethoxy)naphthalen-1-yl)-4-(piperazin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)oxy)-N,N-dimethylpropan-1-amine(54 mg, 100% yield) which was used in the next step withoutpurification. ES+APCI MS m/z 507.3 [M+H]⁺.

Step F:(S)-1-(4-(2-((1-(dimethylamino)propan-2-yl)oxy)-7-(3-(methoxymethoxy)naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

To a suspension of(S)-2-((7-(3-(methoxymethoxy)naphthalen-1-yl)-4-(piperazin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)oxy)-N,N-dimethylpropan-1-amine(54 mg, 0.11 mmol) in dichloromethane (1066 μL, 0.11 mmol) at ambienttemperature was added acryloyl chloride (1279 μL, 0.13 mmol) (freshlyprepared 0.1 M solution in DCM) followed by triethylamine (30 μL, 0.21mmol). The reaction was stirred at ambient temperature for 20 minutes.The mixture was concentrated and the product was purified by columnchromatography (Biotage Isolera, 12G Isco RediSep®, 0-15%methanol/dichloromethane) to afford(S)-1-(4-(2-((1-(dimethylamino)propan-2-yl)oxy)-7-(3-(methoxymethoxy)naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one(51 mg, 0.091 mmol, 85% yield). ES+APCI MS m/z 561.3 [M+H]⁺.

Step G:1-(4-(2-(2-(dimethylamino)ethoxy)-7-(3-hydroxynaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

(S)-1-(4-(2-((1-(dimethylamino)propan-2-yl)oxy)-7-(3-(methoxymethoxy)naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one(51 mg, 0.091 mmol) was added to a vial containing 350 μL of methanoland a few drops of tetrahydrofuran and the reaction vial was capped. HCl(379 μL, 2.3 mmol) (6M aqueous) was added with stirring, and the mixturewas heated to 55° C. for 3 hours. The reaction was cooled andconcentrated under vacuum. A saturated bicarbonate solution was addedand the reaction was extracted with 10% methanol in dichloromethane. Theorganic layers were combined and concentrated. The resulting residue waspurified by silica gel (Biotage Isolera, 4-20% methanol indichloromethane with 1% concentrated ammonium chloride) to provide thetitle product (25.3 mg, 54%). ES+APCI MS m/z 517.2 [M+H]⁺.

¹H NMR (400 MHz, CDCl₃) δ 7.90 (d, 1H, J=8.314 Hz), 7.54 (d, 1H,J=8.021), 7.34 (m, 1H), 7.24 (m, 1H). 6.72 (m, 1H), 6.56-6.48 (m, 2H),6.32 (dd, 1H, J=16.726, 1.858), 5.73 (dd, 1H, J=10.368, 1.858), 5.45 (m,1H), 4.09-3.94 (m, 2H), 3.63 (bs, 2H), 3.47 (bs, 2H), 3.31 (m, 4H), 3.16(bs, 2H), 2.84 (m, 1H), 2.60 (bs, 2H), 2.45 (m, 1H), 2.43 (s, 6H), 1.31(d, 3H, J=6.162 Hz)

Example 9

1-(4-(2-(2-(dimethylamino)ethoxy)-7-(3-hydroxynaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Synthesized according to the method of Example 8, using2-(dimethylamino)ethan-1-ol in place of (S)-1-(dimethylamino)propan-2-olin Step B. ES+APCI MS m/z 503.2 [M+H]⁺.

Example 10

1-(4-(2-(3-(dimethylamino)propoxy)-7-(3-hydroxynaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Synthesized according to the method of Example 8, using3-(dimethylamino)propan-1-ol in place of(S)-1-(dimethylamino)propan-2-ol in Step B. ES+APCI MS m/z 517.3 [M+H]⁺.

Example 11

1-(4-(2-((1-(dimethylamino)propan-2-yl)oxy)-7-(3-hydroxynaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Synthesized according to the method of Example 8, using1-(dimethylamino)propan-2-ol in place of(S)-1-(dimethylamino)propan-2-ol in Step B. ES+APCI MS m/z 517.3 [M+H]⁺.

Example 12

1-(4-(7-(3-hydroxynaphthalen-1-yl)-2-(4-methylpiperazin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Synthesized according to the method of Example 8, using1-methylpiperazine in place of (S)-1-(dimethylamino)propan-2-ol in StepB. ES+APCI MS m/z 514.3 [M+H]⁺.

Example 13

1-(4-(2-(3-(dimethylamino)pyrrolidin-1-yl)-7-(3-hydroxynaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Synthesized according to the method of Example 8, usingN,N-dimethylpyrrolidin-3-amine in place of(S)-1-(dimethylamino)propan-2-ol in Step B. ES+APCI MS m/z 528.3 [M+H]⁺.

Example 14

(S)-1-(4-(7-(3-hydroxynaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2-methylpiperazin-1-yl)prop-2-en-1-one

Synthesized according to the method of Example 8, using benzyl(S)-2-methylpiperazine-1-carboxylate in place of benzylpiperazine-1-carboxylate in Step A and using 2-(dimethylamino)ethan-1-olin place of (S)-1-(dimethylamino)propan-2-ol in Step B. ES+APCI MS m/z517.3 [M+H]⁺.

Example 15

(R)-1-(4-(2-(2-(dimethylamino)ethoxy)-7-(3-hydroxynaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2-methylpiperazin-1-yl)prop-2-en-1-one

Synthesized according to the method of Example 8, substituting benzyl(R)-2-methylpiperazine-1-carboxylate for benzyl piperazine-1-carboxylatein Step A and 2-(dimethylamino)ethan-1-ol for(S)-1-(dimethylamino)propan-2-ol in Step B. ES+APCI MS m/z 517.3 [M+H]⁺.

Example 16

1-(6-(2-(2-(dimethylamino)ethoxy)-7-(3-hydroxynaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2,6-diazaspiro[3.3]heptan-2-yl)prop-2-en-1-one

Synthesized according to the method of Example 8, using benzyl2,6-diazaspiro[3.3]heptane-2-carboxylate in place of benzylpiperazine-1-carboxylate in Step A and substituting2-(dimethylamino)ethan-1-ol in place of (S)-1-(dimethylamino)propan-2-olin Step B. ES+APCI MS m/z 515.3 [M+H]⁺.

Example 17

1-(4-(2-(4-(dimethylamino)piperidin-1-yl)-7-(3-hydroxynaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Synthesized according to the method of Example 8, usingN,N-dimethylpiperidin-4-amine in place of(S)-1-(dimethylamino)propan-2-ol in Step B. ES+APCI MS m/z 580.3 [M+H]⁺.

Example 18

1-(6-(2-((1-(dimethylamino)propan-2-yl)oxy)-7-(3-hydroxynaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2,6-diazaspiro[3.3]heptan-2-yl)prop-2-en-1-one

Synthesized according to the method of Example 8, using benzyl2,6-diazaspiro[3.3]heptane-2-carboxylate in place of benzylpiperazine-1-carboxylate in Step A and substituting1-(dimethylamino)propan-2-ol in place of(S)-1-(dimethylamino)propan-2-ol in Step B. ES+APCI MS m/z 529.3 [M+H]⁺.

Example 19

(R)-1-(4-(2-((1-(dimethylamino)propan-2-yl)oxy)-7-(3-hydroxynaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Synthesized according to the method of Example 8, using(R)-1-(dimethylamino)propan-2-ol in place of(S)-1-(dimethylamino)propan-2-ol in Step B. ES+APCI MS m/z 517.3 [M+H]⁺.

Example 20

1-(6-(2-(3-(dimethylamino)propoxy)-7-(3-hydroxynaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2,6-diazaspiro[3.3]heptan-2-yl)prop-2-en-1-one

Synthesized according to the method of Example 8, using benzyl2,6-diazaspiro[3.3]heptane-2-carboxylate in place of benzylpiperazine-1-carboxylate in Step A and substituting3-(dimethylamino)propan-1-ol in place of(S)-1-(dimethylamino)propan-2-ol in Step B. ES+APCI MS m/z 529.3 [M+H]⁺.

Example 21

1-(4-(2-((4-(dimethylamino)butan-2-yl)oxy)-7-(3-hydroxynaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Synthesized according to the method of Example 8, using4-(dimethylamino)butan-2-ol in place of (S)-1-(dimethylamino)propan-2-olin Step B. ES+APCI MS m/z 531.3 [M+H]⁺.

Example 22

1-(4-(7-(3-hydroxynaphthalen-1-yl)-2-((1-methylpiperidin-4-yl)oxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Synthesized according to the method of Example 8, using1-methylpiperidin-4-ol in place of (S)-1-(dimethylamino)propan-2-ol inStep B. ES+APCI MS m/z 529.3 [M+H]⁺.

Example 23

1-(4-(7-(3-hydroxynaphthalen-1-yl)-2-((1-methylpyrrolidin-3-yl)oxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Synthesized according to the method of Example 8, using1-methylpyrrolidin-3-ol in place of (S)-1-(dimethylamino)propan-2-ol inStep B. ES+APCI MS m/z 515.3 [M+H]⁺.

Example 24

1-(4-(2-((1-(dimethylamino)propan-2-yl)oxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Synthesized according to the method of Example 8, using1-(dimethylamino)propan-2-ol in place of(S)-1-(dimethylamino)propan-2-ol in Step B, using 1-bromo naphthalene inplace of 3-(methoxymethoxy)naphthalen-1-yl trifluoromethanesulfonate instep D, and eliminating Step G. ES+APCI MS m/z 501.3 [M+H]⁺.

Example 25

1-(4-(2-(3-(dimethylamino)propoxy)-7-(1-phenylethyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Synthesized according to the method of Example 8, using3-(dimethylamino)propan-1-ol in place of(S)-1-(dimethylamino)propan-2-ol in Step B, using (1-bromoethyl)benzenein place of 3-(methoxymethoxy)naphthalen-1-yl trifluoromethanesulfonatein step D, and eliminating Step G. ES+APCI MS m/z 559.3 [M+H]⁺.

Example 26

1-(4-(2-(4-(2-hydroxyethyl)piperazin-1-yl)-7-(3-hydroxynaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Synthesized according to the method of Example 8, using2-(piperazin-1-yl)ethyl acetate in place of(S)-1-(dimethylamino)propan-2-ol in Step B. After Step D, the followingsaponification reaction was performed: Benzyl4-(2-(4-(2-acetoxyethyl)piperazin-1-yl)-7-(3-(methoxymethoxy)naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylatewas taken up in THE (5 mL) and 2 M LiGH (1 mL) was added. The mixturewas stirred at ambient temperature for 24 hr. Saturated NH₄Cl was addedand the reaction was extracted with DCM. The combined organic layerswere concentrated and the resulting residue was purified by silica gel(Biotage Isolera Gold, eluting with 0-10% MeOH in DCM) to provide benzyl4-(2-(4-(2-hydroxyethyl)piperazin-1-yl)-7-(3-(methoxymethoxy)naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate.The remainder of the synthesis proceeded as in Example 8, step E.ES+APCI MS m/z 544.3 [M+H]⁺.

Example 27

1-((S)-4-(2-(((R)-1-(dimethylamino)propan-2-yl)oxy)-7-(3-hydroxynaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-3-methylpiperazin-1-yl)prop-2-en-1-one

Synthesized according to the method of Example 8, using benzyl(S)-3-methylpiperazine-1-carboxylate in place of benzylpiperazine-1-carboxylate in Step A and using(R)-1-(dimethylamino)propan-2-ol in place of(S)-1-(dimethylamino)propan-2-ol in Step B. ES+APCI MS m/z 531.3 [M+H]⁺.

Example 28

(S)-1-(4-(2-(2-(dimethylamino)ethoxy)-7-(3-hydroxynaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-3-methylpiperazin-1-yl)prop-2-en-1-one

Synthesized according to the method of Example 8, using benzyl(S)-3-methylpiperazine-1-carboxylate in place of benzylpiperazine-1-carboxylate in Step A and using 2-(dimethylamino)ethan-1-olin place of (S)-1-(dimethylamino)propan-2-ol in Step B. ES+APCI MS m/z517.2 [M+H]⁺.

Example 29

1-(4-(7-(3-hydroxynaphthalen-1-yl)-2-(2-morpholinoethoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Synthesized according to the method of Example 8, using2-morpholinoethan-1-ol in place of (S)-1-(dimethylamino)propan-2-ol inStep B. ES+APCI MS m/z 545.2 [M+H]⁺.

Example 30

1-(4-(7-(3-hydroxynaphthalen-1-yl)-2-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Synthesized according to the method of Example 8, using morpholine inplace of (S)-1-(dimethylamino)propan-2-ol in Step B. ES+APCI MS m/z501.3 [M+H]⁺.

Example 31

1-(4-(7-(3-hydroxynaphthalen-1-yl)-2-(pyrrolidin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Synthesized according to the method of Example 8, using pyrrolidine inplace of (S)-1-(dimethylamino)propan-2-ol in Step B. ES+APCI MS m/z485.2 [M+H]⁺.

Example 32

(R)-1-(4-(7-(3-hydroxynaphthalen-1-yl)-2-((1-(pyrrolidin-1-yl)propan-2-yl)oxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Synthesized according to the method of Example 8, using(R)-1-(pyrrolidin-1-yl)propan-2-ol in place of(S)-1-(dimethylamino)propan-2-ol in Step B. ES+APCI MS m/z 543.4 [M+H]⁺.

Example 33

1-(4-(2-(2-(1,1-dioxidothiomorpholino)ethoxy)-7-(3-hydroxynaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-onetrifluoroacetate Step A: benzyl4-[7-(3-benzyloxy-1-naphthyl)-2-[2-(1,1-dioxo-1,4-thiazinan-4-yl)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate

To a mixture of benzyl4-[7-(3-benzyloxy-1-naphthyl)-2-methylsulfinyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(300 mg, 463.12 μmol, 1.00 eq) and2-(1,1-dioxo-1,4-thiazinan-4-yl)ethanol (166 mg, 926 μmol, 2.00 eq) intoluene (10.0 mL) was added NaOBu-t (133 mg, 1.39 mmol, 3.00 eq), BINAP(57.7 mg, 92.6 μmol, 0.20 eq), Pd₂(dba)₃ (42.4 mg, 46.3 μmol, 0.10 eq).The reaction mixture was stirred at 90° C. for 12 hours under N₂. Thereaction mixture was filtered and the filter cake was washed with DCM(3×10 mL). The filtrate was concentrated under vacuum. The residue waspurified by reverse flash chromatography (40% MeCN in water (0.1% TFA)to give benzyl4-[7-(3-benzyloxy-1-naphthyl)-2-[2-(1,1-dioxo-1,4-thiazinan-4-yl)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(230 mg, 301 μmol, 65.1% yield) as a brown solid. ESI MS m/z 763.5[M+H]⁺.

Step B:4-[2-[2-(1,1-dioxo-1,4-thiazinan-4-yl)ethoxy]-4-piperazin-1-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl]naphthalen-2-ol

To a solution of benzyl4-[7-(3-benzyloxy-1-naphthyl)-2-[2-(1,1-dioxo-1,4-thiazinan-4-yl)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(190 mg, 249 μmol, 1.00 eq) in MeOH (10.0 mL) was added Pd/C (100 mg)under N₂. The suspension was degassed under vacuum and purged withhydrogen several times. The mixture was stirred under hydrogen (15 psi)at 40° C. for 4 hours. The reaction mixture was filtered and thefiltrate was concentrated under vacuum to give4-[2-[2-(1,1-dioxo-1,4-thiazinan-4-yl)ethoxy]-4-piperazin-1-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl]naphthalen-2-ol(90.0 mg, 167 μmol, 67.1% yield) as a brown solid. ESI MS m/z 539.4[M+H]⁺.

Step C:1-[4-[2-[2-(1,1-dioxo-1,4-thiazinan-4-yl)ethoxy]-7-(3-hydroxy-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one

To a solution of4-[2-[2-(1,1-dioxo-1,4-thiazinan-4-yl)ethoxy]-4-piperazin-1-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl]naphthalen-2-ol(90.0 mg, 167 μmol, 1.00 eq) and DIEA (64.8 mg, 501 μmol, 87.5 μL, 3.00eq) in DCM (2.00 mL) was added prop-2-enoyl prop-2-enoate (19.0 mg, 150μmol, 0.90 eq) at −40° C. The reaction mixture was stirred at −40° C.for 0.5 h. The reaction mixture was quenched with 1 mL of MeOH andconcentrated under vacuum. The residue was purified by preparative HPLCcolumn: Phenomenex Synergi C18 150*25*, 10μ; mobile phase: [water (0.1%TFA)-ACN]; B %: 12%-42%, 11 min to give1-[4-[2-[2-(1,1-dioxo-1,4-thiazinan-4-yl)ethoxy]-7-(3-hydroxy-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-onetrifluoroacetate (32.6 mg, 50.2 μmol, 30.0% yield, 91.3% purity) as abrown solid. ESI MS m/z 593.5 [M+H]⁺.

Example 34

1-(4-(2-(3-(1,1-dioxidothiomorpholino)propoxy)-7-(3-hydroxynaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-onetrifluoroacetate

Synthesized according to the method of Example 33, using3-(1,1-dioxo-1,4-thiazinan-4-yl)propan-1-ol in place of2-(1,1-dioxo-1,4-thiazinan-4-yl)ethanol in Step A. ESI MS m/z 607.5[M+H]⁺.

Example 35

1-(4-(7-(3-hydroxynaphthalen-1-yl)-2-(4-morpholinobutoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-onetrifluoroacetate

Synthesized according to the method of Example 33, using4-morpholinobutan-1-ol in place of2-(1,1-dioxo-1,4-thiazinan-4-yl)ethanol in Step A. ESI MS m/z 573.4[M+H]⁺.

Example 36

(R)-1-(4-(2-((1-(4-acetylpiperazin-1-yl)propan-2-yl)oxy)-7-(3-hydroxynaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Synthesized according to the method of Example 33, using1-[4-[(2R)-2-hydroxypropyl]piperazin-1-yl]ethanone in place of2-(1,1-dioxo-1,4-thiazinan-4-yl)ethanol in Step A. ESI MS m/z 600.6[M+H]⁺.

Example 37

1-(4-(2-(2-(4-acetylpiperazin-1-yl)ethoxy)-7-(3-hydroxynaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-oneStep A: benzyl4-[2-[2-(4-acetylpiperazin-1-yl)ethoxy]-7-(3-benzyloxy-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate

To a solution of 1-[4-(2-hydroxyethyl)piperazin-1-yl]ethanone (277 mg,1.61 mmol, 2.60 eq) in THE (8.00 mL) was added NaH (49.4 mg, 1.23 mmol,60% purity, 2.00 eq) at 0° C. The reaction mixture was stirred at 0° C.for 15 minutes. To the mixture was addedbenzyl-4-[7-(3-benzyloxy-1-naphthyl)-2-methylsulfinyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(400 mg, 618 μmol, 1.00 eq) in THE (2.00 mL). The reaction mixture wasstirred at 0° C. for 20 minutes. The reaction mixture was quenched withsaturated NH₄Cl (6 mL) and water (6 mL). The reaction mixture wasextracted with ethyl acetate (3×30 mL). The combined organic layers werewashed with brine (10 mL), dried over Na₂SO₄ and concentrated undervacuum to give benzyl4-[2-[2-(4-acetylpiperazin-1-yl)ethoxy]-7-(3-benzyloxy-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(450 mg, 534 μmol, 86.5% yield, 89.7% purity) as a brown solid. ESI MSm/z 756.3 [M+H]⁺.

Step B:1-[4-[2-[[7-(3-hydroxy-1-naphthyl)-4-piperazin-1-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-2-yl]oxy]ethyl]piperazin-1-yl]ethanone

To a solution of benzyl4-[2-[2-(4-acetylpiperazin-1-yl)ethoxy]-7-(3-benzyloxy-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(200 mg, 264 μmol, 1.00 eq) in THE (10.0 mL) was added Pd/C (100 mg, 10%purity) under N₂. The suspension was degassed under vacuum and purgedwith hydrogen several times. The mixture was stirred under hydrogen (15psi) at 40° C. for 12 hours. The reaction mixture was filtered and thefilter cake was washed with THE (3×5 mL). The filtrate was concentratedunder vacuum to give1-[4-[2-[[7-(3-hydroxy-1-naphthyl)-4-piperazin-1-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-2-yl]oxy]ethyl]piperazin-1-yl]ethanone(80.0 mg, 150 μmol, 56.9% yield) as a brown solid.

Step C:1-[4-[2-[2-(4-acetylpiperazin-1-yl)ethoxy]-7-(3-hydroxy-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one

To a solution of1-[4-[2-[[7-(3-hydroxy-1-naphthyl)-4-piperazin-1-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-2-yl]oxy]ethyl]piperazin-1-yl]ethanone(80.0 mg, 150 μmol, 1.00 eq) and DIEA (58.3 mg, 451 μmol, 78.8 μL, 3.00eq) in DCM (2.00 mL) was added prop-2-enoyl prop-2-enoate (14.2 mg, 113μmol, 0.75 eq) at −40° C. for 0.5 h. The reaction mixture was quenchedwith MeOH (1 mL) and diluted by DCM (20 mL) next washed with water (5mL). The combined organic layers were washed with brine (5 mL), driedover Na₂SO₄ and concentrated under vacuum. The reaction mixture waspurified by preparative HPLC: Phenomenex Gemini 150*25 mm*, 10μ; mobilephase: [water (0.05% ammonia hydroxide v/v)-ACN]; B %: 30%-55%, 10 minto give1-[4-[2-[2-(4-acetylpiperazin-1-yl)ethoxy]-7-(3-hydroxy-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one(13.8 mg, 23.3 μmol, 15.5% yield, 98.7% purity) as a yellow solid. ESIMS m/z 586.3 [M+H]⁺.

Example 38

1-(4-(7-(3-hydroxynaphthalen-1-yl)-2-(3-(piperidin-1-yl)propoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Synthesized according to the method of Example 37, using3-(1-piperidyl)propan-1-ol in place of1-[4-(2-hydroxyethyl)piperazin-1-yl]ethanone in Step A. ESI MS m/z 557.5[M+H]⁺.

Example 39

1-(4-(7-(3-hydroxynaphthalen-1-yl)-2-(3-(pyrrolidin-1-yl)propoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Synthesized according to the method of Example 37, using3-pyrrolidin-1-ylpropan-1-ol in place of1-[4-(2-hydroxyethyl)piperazin-1-yl]ethanone in Step A. ESI MS m/z 543.3[M+H]⁺

Example 40

1-(4-(2-(4-(dimethylamino)butoxy)-7-(3-hydroxynaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Synthesized according to the method of Example 37, using4-(dimethylamino)butan-1-ol in place of1-[4-(2-hydroxyethyl)piperazin-1-yl]ethanone in Step A. ESI MS m/z 531.4[M+H]⁺

Example 41

1-(4-(7-(3-cyclopropyl-5-hydroxyphenyl)-2-(3-morpholinopropoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-onetrifluoroacetate Step A:4-[7-(3-benzyloxy-5-cyclopropyl-phenyl)-2-(3-morpholinopropoxy)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate

To a mixture of benzyl4-[2-(3-morpholinopropoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(400 mg, 805 μmol, 1.00 eq) and1-benzyloxy-3-bromo-5-cyclopropyl-benzene (268 mg, 886 μmol, 1.10 eq) intoluene (10.0 mL) was added2-dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl (RuPhos) (75.2 mg,161 μmol, 0.20 eq), Pd₂(dba)₃ (111 mg, 121 μmol, 0.15 eq) and Cs₂CO₃(656 mg, 2.01 mmol, 2.50 eq). The reaction mixture was stirred at 90° C.for 12 hours under N₂. The mixture was added to water (15 mL) andextracted with DCM (2×15 mL). The combined organic layers were driedover Na₂SO₄, filtered and concentrated. The residue was purified bychromatography (SiO₂, Petroleum ether/Ethyl acetate=3:1 toDichloromethane:Methanol=10:1) to give benzyl4-[7-(3-benzyloxy-5-cyclopropyl-phenyl)-2-(3-morpholinopropoxy)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(170 mg, 230 μmol, 28.5% yield, 97.2% purity) as brown oil. ESI MS m/z719.6 [M+H]⁺.

Step B:3-cyclopropyl-5-[2-(3-morpholinopropoxy)-4-piperazin-1-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl]phenol

To a mixture of benzyl4-[7-(3-benzyloxy-5-cyclopropyl-phenyl)-2-(3-morpholinopropoxy)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(150 mg, 209 μmol, 1.00 eq) in MeOH (10.0 mL) was added Pd/C (150 mg,10% purity) and CH₃COOH (25.1 mg, 417.3 μmol, 23.9 μL, 2.00 eq). Thesuspension was degassed under vacuum and purged with hydrogen severaltimes. The mixture was stirred under hydrogen (15 Psi) at 40° C. for 2hours. The reaction mixture was filtered through Celite® and thefiltrate was concentrated. The product3-cyclopropyl-5-[2-(3-morpholinopropoxy)-4-piperazin-1-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl]phenoldiacetate (80.0 mg, 130 μmol, 62.4% yield) was obtained as yellow solid.ESI MS m/z 495.2 [M+H]⁺.

Step C:1-[4-[7-(3-cyclopropyl-5-hydroxy-phenyl)-2-(3-morpholinopropoxy)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one

To a mixture of3-cyclopropyl-5-[2-(3-morpholinopropoxy)-4-piperazin-1-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl]phenoldiacetate (80.0 mg, 130 μmol, 1.00 eq) in DCM (2.00 mL) was added DIEA(168 mg, 1.30 mmol, 227 μL, 10.0 eq) and prop-2-enoyl prop-2-enoate(13.1 mg, 104 μmol, 0.80 eq) at −78° C., the reaction mixture wasstirred at −78° C. for 0.5 hour. The reaction mixture was quenched withMeOH (2 eq, 10 mg), then concentrated. The residue was purified bypreparative HPLC (Instrument: GX-K; Column: Phenomenex Synergi C18150*25*, 10μ; Conditions: water (0.1% TFA)-ACN; Begin B: 8; End B: 38;Gradient Time (min): 11; 100% B Hold Time (min): 2; FlowRate (mL/min):25). The isolated product was concentrated by lyophilization. Theproduct1-[4-[7-(3-cyclopropyl-5-hydroxy-phenyl)-2-(3-morpholinopropoxy)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-onetrifluoroacetate (21.5 mg, 31.1 μmol, 23.9% yield, 95.8% purity) wasobtained as yellow solid. ESI MS m/z 549.5 [M+H]⁺.

Example 42

1-(4-(7-(2-fluoro-5-hydroxyphenyl)-2-(3-morpholinopropoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Synthesized according to the method of Example 41, using4-(benzyloxy)-2-bromo-1-fluorobenzene in place of1-benzyloxy-3-bromo-5-cyclopropyl-benzene in Step A. ESI MS m/z 527.4[M+H]⁺.

Example 43

1-(4-(7-(3-hydroxy-6-methylnaphthalen-1-yl)-2-(3-morpholinopropoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-oneStep A: benzyl4-[7-(3-methoxy-6-methyl-1-naphthyl)-2-(3-morpholinopropoxy)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate

A mixture of benzyl4-[2-(3-morpholinopropoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(500 mg, 1.01 mmol, 1.00 eq),(3-methoxy-6-methyl-1-naphthyl)trifluoromethanesulfonate (483 mg, 1.51mmol, 1.50 eq), Cs₂CO₃ (820 mg, 2.52 mmol, 2.50 eq),2-dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl (RuPhos) (93.9 mg,201.3 μmol, 0.20 eq) and Pd₂(dba)₃ (92.2 mg, 100 μmol, 0.10 eq) intoluene (3.00 mL) was stirred at 90° C. for 10 hours. The mixture wasdiluted with ethyl acetate (50.0 mL). The precipitate was removed byfiltration, and the filtrate was concentrated under vacuum. The residuewas purified by reversed phase column chromatography over silica gel(0.1% TFA water/acetonitrile). The desired fractions were combined andbasified with saturated aqueous sodium bicarbonate (2.00 mL), thenconcentrated under vacuum. The residue was extracted with ethyl acetate(2×100 mL). The combined extracts were washed with brine (1×100 mL),dried over sodium sulfate, filtered and concentrated under vacuum togive benzyl4-[7-(3-methoxy-6-methyl-1-naphthyl)-2-(3-morpholinopropoxy)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(400. mg, 599 μmol, 59.4% yield, 100% purity) as a yellow solid. ESI MSm/z 667.6 [M+H]⁺.

Step B:4-[3-[[7-(3-methoxy-6-methyl-1-naphthyl)-4-piperazin-1-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-2-yl]oxy]propyl]morpholine

To a solution of benzyl4-[7-(3-methoxy-6-methyl-1-naphthyl)-2-(3-morpholinopropoxy)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(370 mg, 554 μmol, 1.00 eq) in MeOH (10.0 mL) was added Pd—C (100 mg,10% purity) and AcOH (66.6 mg, 1.11 mmol, 2.00 eq) under N₂. Thesuspension was degassed under vacuum and purged with hydrogen severaltimes. The mixture was stirred under hydrogen (15 psi) at 40° C. for 2hours. The reaction mixture was filtered and concentrated in vacuum toprovide4-[3-[[7-(3-methoxy-6-methyl-1-naphthyl)-4-piperazin-1-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-2-yl]oxy]propyl]morpholine(295 mg, 553 μmol, 99.8% yield) as a yellow solid which was useddirectly in the next step without purification. ESI MS m/z 533.6 [M+H]⁺

Step C:1-[4-[7-(3-methoxy-6-methyl-1-naphthyl)-2-(3-morpholinopropoxy)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one

To a mixture of prop-2-enoyl prop-2-enoate (56.8 mg, 450 μmol, 0.80 eq)and DIEA (727 mg, 5.63 mmol, 983 μL, 10.0 eq) in DCM (2.00 mL) was addeda solution of4-[3-[[7-(3-methoxy-6-methyl-1-naphthyl)-4-piperazin-1-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-2-yl]oxy]propyl]morpholine(300 mg, 563 μmol, 1.00 eq) DCM (1.00 mL) at −40° C. under a nitrogenatmosphere. The mixture was stirred for 1 hour. The reaction mixture wasquenched by addition of MeOH (50 μL) at −40° C., diluted with water(10.0 mL), extracted with DCM (10.0 mL), dried over Na₂SO₄, filtered andconcentrated under reduced pressure to provide1-[4-[7-(3-methoxy-6-methyl-1-naphthyl)-2-(3-morpholinopropoxy)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one(270 mg, 460 μmol, 81.7% yield) ESI MS m/z 587.6 [M+H]⁺.

Step D:1-[4-[7-(3-hydroxy-6-methyl-1-naphthyl)-2-(3-morpholinopropoxy)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one

To a solution of1-[4-[7-(3-methoxy-6-methyl-1-naphthyl)-2-(3-morpholinopropoxy)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one(100 mg, 170 μmol, 1.00 eq) in DCM (3.00 mL) was added BBr₃ (213 mg, 852μmol, 82.1 μL, 5.00 eq) at −78° C. The mixture was stirred at 0° C. for1 hour. The mixture was cooled to −78° C. and diluted with DCM (20.0mL), quenched by addition of saturated sodium bicarbonate solution (5.00mL) and stirred at −78° C. for 10 mins, then warmed to 0° C. The mixturewas extracted with DCM (2×15.0 mL), washed with brine (1×20.0 mL), driedover Na₂SO₄, filtered and concentrated under vacuum. The residue waspurified by preparative HPLC (column: Phenomenex Gemini C18 250*50 mm*,10μ; mobile phase: [water (0.05% ammonia hydroxide v/v)-ACN]; B %:27%-57%, 12 min) to provide1-[4-[7-(3-hydroxy-6-methyl-1-naphthyl)-2-(3-morpholinopropoxy)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one(11.0 mg, 18.6 μmol, 10.9% yield, 97.0% purity) as a brown solid. ESI MSm/z 573.6 [M+H]⁺.

Example 44

1-(4-(7-(5-methyl-1H-indazol-4-yl)-2-(3-morpholinopropoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-oneStep A: benzyl4-[7-[5-methyl-1-(2-trimethylsilylethoxymethyl)indazol-4-yl]-2-(3-morpholinopropoxy)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate

A mixture of benzyl4-[2-(3-morpholinopropoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(500 mg, 1.01 mmol, 1.00 eq), 2-[(4-bromo-5-methyl-indazol-1-yl)methoxy]ethyl-trimethylsilane (448 mg, 1.31 mmol, 1.30 eq), Cs₂CO₃ (822 mg, 2.53mmol, 2.50 eq), Pd₂(dba)₃ (138 mg, 151 μmol, 0.15 eq) and2-dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl (RuPhos) (94.3 mg,202 μmol, 0.20 eq) in toluene (20.0 mL) was degassed and purged withnitrogen 3 times, and stirred at 90° C. for 10 hours under a nitrogenatmosphere. The reaction mixture was diluted with water (50 mL) andextracted with ethyl acetate (3×100 mL). The combined organic layerswere washed with brine (3×50.0 mL), dried over Na₂SO₄, filtered andconcentrated under reduced pressure. The residue was purified byreversed phase HPLC (0.1% TFA water/acetonitrile) to provide benzyl4-[7-[5-methyl-1-(2-trimethylsilylethoxymethyl)indazol-4-yl]-2-(3-morpholinopropoxy)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(420 mg, 554 μmol, 54.9% yield) as a yellow oil. ESI MS m/z 757.6[M+H]⁺.

Step B: tert-butyl4-[7-[5-methyl-1-(2-trimethylsilylethoxymethyl)indazol-4-yl]-2-(3-morpholinopropoxy)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate

To a solution of benzyl 4-[7-[5-methyl-1-(2-trimethylsilylethoxymethyl)indazol-4-yl]-2-(3-morpholinopropoxy)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(370 mg, 488 μmol, 1.00 eq) in MeOH (10.0 mL) was added triethylamine(98.9 mg, 977 μmol, 135 μL, 2.00 eq), Pd/C (100 mg, 10% purity) andtert-butoxycarbonyl tert-butyl carbonate (213 mg, 977 μmol, 224 μL, 2.00eq) under N₂. The suspension was degassed under vacuum and purged withhydrogen several times. The mixture was stirred under hydrogen (15 psi)at 40° C. for 2 hours. The reaction mixture was filtrated andconcentrated under vacuum. The residue was purified by columnchromatography (SiO₂, DCM/MeOH=1:0 to 10:1) to provide tert-butyl4-[7-[5-methyl-1-(2-trimethylsilylethoxymethyl)indazol-4-yl]-2-(3-morpholinopropoxy)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(340 mg, 470 μmol, 96.2% yield) as a brown oil. ESI MS m/z 723.5 [M+H]⁺.

Step C:4-[3-[[7-(5-methyl-1H-indazol-4-yl)-4-piperazin-1-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-2-yl]oxy]propyl]morpholineTrifluoroacetate

To a solution of tert-butyl4-[7-[5-methyl-1-(2-trimethylsilylethoxymethyl)indazol-4-yl]-2-(3-morpholinopropoxy)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(150 mg, 207 μmol, 1.00 eq) in DCM (500 μL) was added TFA (354 mg, 3.11mmol, 230 μL, 15.0 eq). The mixture was stirred at 25° C. for 1 hour.The reaction mixture was concentrated in vacuum to provide4-[3-[[7-(5-methyl-1H-indazol-4-yl)-4-piperazin-1-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-2-yl]oxy]propyl]morpholinetrifluoroacetate (125 mg, 206 μmol, 99.3% yield) as a brown oil and useddirectly in the next step without purification. ESI MS m/z 493.4 [M+H]⁺.

Step D1-[4-[7-(5-methyl-H-indazol-4-yl)-2-(3-morpholinopropoxy)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one

To a mixture of4-[3-[[7-(5-methyl-1H-indazol-4-yl)-4-piperazin-1-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-2-yl]oxy]propyl]morpholinetrifluoroacetate (120 mg, 197 μmol, 1.00 eq, TFA) and DIEA (255 mg, 1.98mmol, 345 μL, 10.0 eq) in dichloromethane (2.00 mL) was added a solutionof prop-2-enoyl prop-2-enoate (19.9 mg, 158 μmol, 0.80 eq)dichloromethane (1.00 mL) at −40° C. under nitrogen atmosphere. Themixture was stirred for 1 hour. The reaction mixture was quenched byaddition of MeOH (50.0 μL) at −40° C., diluted with water (10.0 mL),extracted with dichloromethane (10.0 mL), dried over Na₂SO₄, filteredand concentrated under reduced pressure. The residue was purified bypreparative HPLC (column: Phenomenex Gemini 150*25 mm*, 10μ; mobilephase: [water (0.05% ammonia hydroxide v/v)-ACN]; B %: 30%-60%, 10 min)to provide1-[4-[7-(5-methyl-1H-indazol-4-yl)-2-(3-morpholinopropoxy)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one(19.0 mg, 34.4 μmol, 17.4% yield, 99.0% purity) as a white solid. ESI MSm/z 547.5 [M+H]⁺.

Example 45

1-((1R,5S)-3-(2-((1-(dimethylamino)propan-2-yl)oxy)-7-(3-hydroxynaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)prop-2-en-1-oneStep A: Tert-butyl3-(7-benzyl-2-chloro-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

To a mixture of7-benzyl-2,4-dichloro-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine (920 mg,3.13 mmol, 1.00 eq) and tert-butyl3,8-diazabicyclo[3.2.1]octane-8-carboxylate (677 mg, 3.19 mmol, 1.02 eq)in DMSO (18.0 mL) was added DIEA (1.21 g, 9.39 mmol, 1.64 mL, 3.00 eq).The reaction mixture was stirred at 60° C. for 1 hour. The mixture wasdiluted with extracted with EtOAc (3×20 mL), washed with water (10 mL),1N HCl (5 mL), NaHCO₃ (15 mL), and brine (15 mL). The combined organiclayers were dried over Na₂SO₄, filtered and concentrated under vacuum togive tert-butyl3-(7-benzyl-2-chloro-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate(1.30 g, 2.41 mmol, 76.9% yield, 87.0% purity) as a brown oil which wasused directly in the next step without further purification. ESI MS m/z470.2 [M+H]⁺.

Step B: tert-butyl3-[7-benzyl-2-[2-(dimethylamino)-1-methyl-ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

To a solution of 1-(dimethylamino)propan-2-ol (857 mg, 8.31 mmol, 942μL, 3.00 eq) in THE (40.0 mL) was added NaH (222 mg, 5.54 mmol, 60.0%purity, 2.00 eq) at 15° C. under N₂. After stirring at 15° C. for 0.5hour, tert-butyl3-(7-benzyl-2-chloro-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate(1.30 g, 2.77 mmol, 1.00 eq) was added. The mixture was stirred at 100°C. for 12 hours in a sealed tube. The reaction was slowly quenched withwater (3 mL) and then concentrated under vacuum. The residue waspurified by column chromatography (DCM/MeOH 60:1 to 10:1) to givetert-butyl3-[7-benzyl-2-[2-(dimethylamino)-1-methyl-ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate(700 mg, 1.07 mmol, 38.8% yield, 82.4% purity) as a yellow oil.

Step C: tert-butyl3-[2-[2-(dimethylamino)-1-methyl-ethoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

To a solution of tert-butyl3-[7-benzyl-2-[2-(dimethylamino)-1-methyl-ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate(700 mg, 1.30 mmol, 1.00 eq) in MeOH (30.0 mL) was added Pd/C (200 mg)under N₂. The suspension was degassed under vacuum and purged withhydrogen 4 times. The mixture was stirred under hydrogen (50 psi) at 40°C. for 12 hours. The mixture was concentrated under vacuum. The residuewas purified by column chromatography (DCM/MeOH 50:1 to 5:1) to givetert-butyl3-[2-[2-(dimethylamino)-1-methyl-ethoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate(500 mg, 952 μmol, 73.2% yield, 85.0% purity) as a yellow oil.

Step D: Tert-butyl3-[7-(3-benzyloxy-1-naphthyl)-2-[2-(dimethylamino)-1-methyl-ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

Pd₂(dba)₃ (84.1 mg, 91.8 μmol, 0.10 eq) was added to a solution oftert-butyl3-[2-[2-(dimethylamino)-1-methyl-ethoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate(410 mg, 918 μmol, 1.00 eq), 3-benzyloxy-1-bromo-naphthalene (293 mg,936 μmol, 1.02 eq), 2-dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl(RuPhos) (85.7 mg, 184 μmol, 0.20 eq) and Cs₂CO₃ (897 mg, 2.75 mmol,3.00 eq) in dioxane (9.00 mL). The reaction mixture was stirred at 100°C. for 7 hours under N₂ and then concentrated under vacuum. The residuewas diluted with water (5 mL) and extracted with DCM (2×20 mL). Theorganic layers were dried over Na₂SO₄, filtered and concentrated undervacuum. The residue was purified by column chromatography (DCM/MeOH100:1 to 20:1) to give tert-butyl3-[7-(3-benzyloxy-1-naphthyl)-2-[2-(dimethylamino)-1-methyl-ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate(317 mg, 441 μmol, 48.1% yield, 94.5% purity) as a yellow oil. ESI MSm/z 679.2 [M+H]⁺.

Step E: tert-butyl3-[2-[2-(dimethylamino)-1-methyl-ethoxy]-7-(3-hydroxy-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

To a solution of tert-butyl3-[7-(3-benzyloxy-1-naphthyl)-2-[2-(dimethylamino)-1-methyl-ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate(340 mg, 501 μmol, 1.00 eq) in MeOH (6.80 mL) was added Pd/C (120 mg).The suspension was degassed under vacuum and purged with hydrogen 4times. The mixture was stirred under hydrogen (15 psi) at 40° C. for 1.5hours. The mixture was concentrated under vacuum to give tert-butyl3-[2-[2-(dimethylamino)-1-methyl-ethoxy]-7-(3-hydroxy-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate(210 mg, 316 μmol, 63.1% yield, 88.6% purity) as a yellow solid whichwas used directly in the next step without further purification. ESI MSm/z 589.3 [M+H]⁺.

Step F:4-[4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-2-[2-(dimethylamino)-1-methyl-ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl]naphthalen-2-oltrifluoroacetate

To a solution of tert-butyl3-[2-[2-(dimethylamino)-1-methyl-ethoxy]-7-(3-hydroxy-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate(180 mg, 306 μmol, 1.00 eq) in DCM (230 μL) was added TFA (349 mg, 3.06mmol, 226 μL, 10.0 eq). The reaction mixture was stirred at 18° C. for0.5 hour. The mixture was concentrated under vacuum to give4-[4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-2-[2-(dimethylamino)-1-methyl-ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl]naphthalen-2-oltrifluoroacetate (528 mg, crude) as a red oil which was used directly inthe next step without further purification. ESI MS m/z 489.2 [M+H]⁺.

Step G:1-[3-[2-[2-(dimethylamino)-1-methyl-ethoxy]-7-(3-hydroxy-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]prop-2-en-1-one

To a solution of4-[4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-2-[2-(dimethylamino)-1-methyl-ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl]naphthalen-2-oltrifluoroacetate (149 mg, 306 μmol, 1.00 eq) and DIEA (1.36 g, 10.5mmol, 1.84 mL, 34.5 eq) in DCM (1.50 mL) was added prop-2-enoylprop-2-enoate (30.9 mg, 245 μmol, 0.80 eq) dropwise at −50° C. Themixture was stirred at −40 and then −20° C. for 30 minutes. The reactionwas quenched with MeOH (19.6 mg) and concentrated under vacuum. Theresidue was purified by preparative TLC (DCM/MeOH 7:1) to give1-[3-[2-[2-(dimethylamino)-1-methyl-ethoxy]-7-(3-hydroxy-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]prop-2-en-1-one(18.9 mg, 32.8 μmol, 10.7% yield, 94.3% purity) as a yellow solid. ESIMS m/z 543.3 [M+H]⁺.

Example 46

1-((1R,5S)-8-(2-((1-(dimethylamino)propan-2-yl)oxy)-7-(3-hydroxynaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)prop-2-en-1-one

Synthesized according to the method of Example 4, using tert-butyl(1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate in place tert-butyl3,8-diazabicyclo[3.2.1]octane-8-carboxylate in Step A. ESI MS m/z 543.4[M+H]⁺.

Example 47

1-(4-(2-(2-(dimethylamino)ethoxy)-7-(3-hydroxynaphthalen-1-yl)-8-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-oneStep A: Ethyl 2-(benzylamino)propanoate

To a solution of ethyl 2-bromopropanoate (30.0 g, 165 mmol, 21.6 mL,1.00 eq), BnNH₂ (23.1 g, 215 mmol, 23.6 mL, 1.30 eq) in MeCN (600 mL)was added K₂CO₃ (45.8 g, 331 mmol, 2.00 eq). The mixture was stirred at80° C. for 2 hour. The reaction mixture was filtered and the filter cakewas washed with DCM (300 mL). The filtrated was concentrated undervacuum. The residue was purified by silica gel chromatography (diethylether:ethyl acetate=10:1 to 4:1) to give ethyl 2-(benzylamino)propanoate(34.0 g, 163 mmol, 98.4% yield, 99.4% purity) a colorless oil.

Step B: ethyl 4-[benzyl-(2-ethoxy-1-methyl-2-oxo-ethyl)amino]butanoate

To a solution of ethyl 2-(benzylamino)propanoate (31.0 g, 150 mmol, 1.00eq) and ethyl 4-bromobutanoate (87.5 g, 449 mmol, 64.4 mL, 3.00 eq) inMeCN (600 mL) and water (60.0 mL) was added Cs₂CO₃ (97.5 g, 299.12 mmol,2.00 eq) and KI (4.97 g, 29.9 mmol, 0.20 eq). The reaction mixture wasstirred at 80-90° C. for 40 hours. The reaction mixture was filtered andthe filter cake was washed with DCM (2×100 mL). The filtrate wasconcentrated under vacuum. The residue was dissolved in DCM (300 mL) andwashed with brine (80 mL), dried over Na₂SO₄ and concentrated undervacuum. The residue was purified by flash silica gel chromatography(diethyl ether:ethyl acetate=1:0 to 20:1) to give ethyl4-[benzyl-(2-ethoxy-1-methyl-2-oxo-ethyl)amino]butanoate (28.0 g, 87.1mmol, 58.3% yield) as a yellow oil.

Step C: ethyl 1-benzyl-2-methyl-3-oxo-piperidine-4-carboxylate

To a solution of ethyl4-[benzyl-(2-ethoxy-1-methyl-2-oxo-ethyl)amino]butanoate (28.0 g, 87.1mmol, 1.00 eq) in THE (600 mL) was added tBuOK (19.6 g, 174 mmol, 2.00eq). The reaction mixture was stirred at 18° C. for 1 hour. The reactionmixture was quenched with water (100 mL) and extracted with MTBE (3×300mL) and DCM (2×200 mL). The combined organic layers were washed withbrine, dried over Na₂SO₄ and concentrated under vacuum. The crudeproduct was purified by silica gel chromatography (diethyl ether:ethylacetate=100:1 to 20:1) to give ethyl1-benzyl-2-methyl-3-oxo-piperidine-4-carboxylate (20.0 g, 58.8 mmol,67.5% yield, 81.0% purity) as a yellow oil. ESI MS m/z 276.0 [M+H]⁺.

Step D:7-benzyl-8-methyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-2,4-diol

To EtOH (400 mL) was added Na (3.76 g, 163 mmol, 3.88 mL, 2.50 eq). Thereaction mixture was stirred at 20° C. for 0.5 hour. To the mixture wasadded ethyl 1-benzyl-2-methyl-3-oxo-piperidine-4-carboxylate (18.0 g,65.4 mmol, 1.00 eq) and UREA (9.82 g, 163 mmol, 8.77 mL, 2.50 eq) andthe reaction mixture was stirred at 80° C. for 80 hours. The solvent wasremoved under vacuum. The residue was dissolved in water (100 mL) andwashed with MTBE (3×50 mL). The aqueous phase was adjusted to pH 6-7with HCl (15 mL, 12 M). The mixture was filtered and the filter cake waswashed with water (30 mL) and dried in vacuum to give7-benzyl-8-methyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-2,4-diol (12.0g, 44.2 mmol, 67.7% yield, 100% purity) was obtained as a brown solid.ESI MS m/z 272.0 [M+H]⁺.

Step E:benzyl-2,4-dichloro-8-methyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine

A mixture of7-benzyl-8-methyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-2,4-diol (5.00g, 18.4 mmol, 1.00 eq) in POCl₃ (305 g, 1.99 mol, 185 mL, 108 eq) washeated to 110° C. for 12 hours. The solvent was removed under vacuum.The residue was dissolved in DCM (500 mL) and poured into saturatedNaHCO₃ (200 mL) while keeping the pH greater than 7. The organic layerwas washed with brine (50 mL), dried over Na₂SO₄. The solution wasfiltered through a pad of silica gel and the filter cake was washed withDCM (3×400 mL). The combined organic layers were concentrated undervacuum to give7-benzyl-2,4-dichloro-8-methyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine(4.50 g, 14.6 mmol, 79.2% yield) as a brown oil.

Step F:4-(7-benzyl-2-chloro-8-methyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate

To a solution of7-benzyl-2,4-dichloro-8-methyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine(3.00 g, 9.73 mmol, 1.00 eq) and DIEA (2.52 g, 19.5 mmol, 3.40 mL, 2.00eq) in dioxane (60.0 mL) was added tert-butyl piperazine-1-carboxylate(1.90 g, 10.2 mmol, 1.05 eq). The reaction mixture was stirred at 60° C.for 12 hours. The solvent was removed under vacuum. The residue waspurified by silica gel chromatography (diethyl ether:ethyl acetate=2:1)to give tert-butyl4-(7-benzyl-2-chloro-8-methyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(3.30 g, 7.15 mmol, 73.5% yield, 99.3% purity) as a yellow solid. ESI MSm/z 458.1 [M+H]⁺.

Step G:tert-butyl-4-[7-benzyl-2-[2-(dimethylamino)ethoxy]-8-methyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate

To a solution of 2-(dimethylamino)ethanol (583 mg, 6.54 mmol, 655 μL,3.00 eq) in toluene (20.0 mL) was added Pd(OAc)₂ (48.9 mg, 218 μmol,0.10 eq),tert-butyl-4-(7-benzyl-2-chloro-8-methyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(1.00 g, 2.18 mmol, 1.00 eq), Cs₂CO₃ (2.13 g, 6.54 mmol, 3.00 eq) andBINAP (272 mg, 436 μmol, 0.20 eq). The reaction mixture was stirred at110° C. for 3 hours under N₂. The reaction mixture was concentratedunder vacuum. The residue was dissolved in water (10 mL) and extractedwith DCM (3×40 mL). The combined organic layers were washed with brine,dried over Na₂SO₄ and concentrated under vacuum. The residue waspurified by silica gel chromatography (diethyl ether:ethyl acetate=5:1to 2:1 then DCM:MeOH=50:1 to 5:1) to givetert-butyl-4-[7-benzyl-2-[2-(dimethylamino)ethoxy]-8-methyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(900 mg, 1.76 mmol, 80.8% yield) as a brown solid. ESI MS m/z 511.2[M+H]⁺.

Step H: tert-butyl4-[2-[2-(dimethylamino)ethoxy]-8-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate

To a solution of tert-butyl4-[7-benzyl-2-[2-(dimethylamino)ethoxy]-8-methyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(800 mg, 1.57 mmol, 1.00 eq) in MeOH (20.0 mL) was added Pd/C (100 mg)under N₂. The suspension was degassed under vacuum and purged withhydrogen several times. The mixture was stirred under hydrogen (50 psi)at 40° C. for 12 hours. The reaction mixture was filtered and the filtercake was washed with MeOH (3×200 mL). The filtrate was concentratedunder vacuum to give tert-butyl4-[2-[2-(dimethylamino)ethoxy]-8-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(450 mg, 1.07 mmol, 68.2% yield) as brown oil which was used for nextstep without further purification. ESI MS m/z 421.3 [M+H]⁺.

Step I: tert-butyl4-[7-(3-benzyloxy-1-naphthyl)-2-[2-(dimethylamino)ethoxy]-8-methyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate

To a mixture of tert-butyl4-[2-[2-(dimethylamino)ethoxy]-8-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(380 mg, 904 μmol, 1.00 eq) and 3-benzyloxy-1-bromo-naphthalene (311 mg,994 μmol, 1.10 eq) in dioxane (8.00 mL), Cs₂CO₃ (883 mg, 2.71 mmol, 3.00eq) and 2-dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl (RuPhos)(84.3 mg, 181 μmol, 0.20 eq) and Pd₂(dba)₃ (82.7 mg, 90.4 μmol, 0.10 eq)were added. The reaction mixture was stirred at 90° C. for 12 h underN₂. The reaction mixture was concentrated under vacuum. The residue waspartitioned between DCM (50 mL) and water (20 mL). The reaction mixturewas extracted with DCM (50 mL). The combined organic layers were washedwith brine (10 mL), dried over Na₂SO₄ and concentrated under vacuum. Theresidue was purified by silica gel chromatography (diethyl ether:ethylacetate=5:1 then DCM:MeOH=100:1 to 5:1), followed by purification of theisolated product by preparative TLC (DCM:MeOH=10:1) to give tert-butyl4-[7-(3-benzyloxy-1-naphthyl)-2-[2-(dimethylamino)ethoxy]-8-methyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(200 mg, 306 μmol, 33.9% yield) as brown solid. ESI MS m/z 653.4 [M+H]⁺.

Step J:4-[2-[2-(dimethylaminoethoxy]-8-methyl-4-piperazin-1-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl]naphthalen-2-olbis-trifluoroacetate

To a solution of tert-butyl4-[2-[2-(dimethylamino)ethoxy]-7-(3-hydroxy-1-naphthyl)-8-methyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(100 mg, 177 μmol, 1.00 eq) in DCM (130.00 μL) was added TFA (202 mg,1.78 mmol, 132 μL, 10.00 eq). The reaction mixture was stirred at 20° C.for 1 hour. The solvent was removed under vacuum to provide4-[2-[2-(dimethylamino)ethoxy]-8-methyl-4-piperazin-1-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl]naphthalen-2-olbis-trifluoroacetate (175.00 mg) as a brown oil which was used in thenext step without further purification.

Step K:1-[4-[2-[2-(dimethylamino)ethoxy]-7-(3-hydroxy-1-naphthyl)-8-methyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one

To a solution of4-[2-[2-(dimethylamino)ethoxy]-8-methyl-4-piperazin-1-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl]naphthalen-2-olbis-trifluoroacetate (97.4 mg, 141 μmol, 1.00 eq) in DCM (500.00 μL) wasadded DIEA (222 mg, 1.72 mmol, 300 μL, 12.2 eq) and prop-2-enoylprop-2-enoate (14.2 mg, 113 μmol, 0.80 eq) at −40° C. The reactionmixture was stirred at −40° C. for 0.5 h. The reaction mixture wasquenched with a drop of MeOH and concentrated under vacuum. The residuewas purified by preparative TLC (DCM:MeOH=10:1) and then by preparativeHPLC (column: Phenomenex Synergi C18 150*25*, 10μ; mobile phase: [water(0.1% TFA)-ACN]; B %: 15%-45%, 13 min) to give1-[4-[2-[2-(dimethylamino)ethoxy]-7-(3-hydroxy-1-naphthyl)-8-methyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one(10.7 mg, 20.7 μmol, three steps 6.8% yield) as a brown oil. ESI MS m/z517.2 [M+H]⁺.

Example 48

1-(4-(2-(2-(dimethylamino)ethoxy)-7-(3-hydroxynaphthalen-1-yl)-6-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-oneTrifluoroacetate Step A: ethyl4-[benzyl-(2-ethoxy-2-oxo-ethyl)amino]pentanoate

A solution of ethyl 4-oxopentanoate (47.0 g, 326 mmol, 46.5 mL, 1.50eq), ethyl 2-(benzylamino)acetate (42.0 g, 217.3 mmol, 1.00 eq) and AcOH(13.0 g, 217 mmol, 12.4 mL, 1.00 eq) in DCM (800 mL) was stirred at12-18° C. for 30 min, then cooled at 0-5° C., NaBH(OAc)₃ (138 g, 652mmol, 3.00 eq) was added portion-wise. The mixture was warmed to 10-18°C. and stirred for 16 hours. The reaction mixture was quenched withwater (1000 mL) and extracted with DCM (2×500 mL). The combined organicphases were dried and concentrated to dryness. The residue was purifiedby silica gel column eluting with diethyl ether/ethyl acetate (60:1 to40:1) to provide ethyl 4-[benzyl-(2-ethoxy-2-oxo-ethyl)amino]pentanoate(42.0 g, 91.5 mmol, 42.1% yield, 70% purity) as colorless oil. ESI MSm/z 322.2 [M+H]⁺.

Step B: ethyl 1-benzyl-2-methyl-5-oxo-piperidine-4-carboxylate

A solution of ethyl 4-[benzyl-(2-ethoxy-2-oxo-ethyl)amino]pentanoate(37.00 g, 115.12 mmol, 1.00 eq) and t-BuOK (16.8 g, 150 mmol, 1.30 eq)in toluene (30.0 mL) was stirred at 25° C. for 5 hours. The reaction wasquenched with water (50 mL) and extracted with ethyl acetate (2×30 mL).The combined organic extracts were dried and concentrated to dryness toprovide ethyl 1-benzyl-2-methyl-5-oxo-piperidine-4-carboxylate (14.6 g,53.0 mmol, 46% yield) as yellow oil which was used directly in the nextstep.

Step C:7-benzyl-6-methyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-2,4-diol

Na (3.05 g, 133 mmol, 3.14 mL, 2.50 eq) was dissolved in EtOH (280 mL),and then ethyl 1-benzyl-2-methyl-5-oxo-piperidine-4-carboxylate (14.6 g,53.0 mmol, 1.00 eq) and urea (7.96 g, 133 mmol, 7.11 mL, 2.50 eq) wereadded. The reaction mixture was heated to reflux (78° C.) for 16 hrsunder N₂. The reaction mixture was concentrated to dryness. The residuewas dissolved in water (100 mL), washed with MTBE (100 mL). The pH ofthe water phase was adjusted to pH 6-7 with 6N HCl (2 mL). The resultingsolid was collected by filtration and dried under vacuum at 60° C. toprovide7-benzyl-6-methyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-2,4-diol (5.00g, 17.1 mmol, 32.3% yield, 93% purity) as light yellow solid.

Step D:7-benzyl-2,4-dichloro-6-methyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine

POCl₃ (49.5 g, 323 mmol, 30.0 mL, 58.4 eq) and7-benzyl-6-methyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-2,4-diol (1.50g, 5.53 mmol, 1.00 eq) were heated to 100° C. under reflux for 12 hours.The reaction was concentrated to dryness to remove POCl₃. The residuewas dissolved in DCM (40 mL) and washed with saturated NaHCO₃aqueous/saturated aqueous Na₂CO₃ (1/1, 60 mL). The mixture was filteredand the organic layers were dried over Na₂SO₄, filtered and concentratedunder vacuum to give7-benzyl-2,4-dichloro-6-methyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine(2.08 g, crude) as a brown solid which was used directly in the nextstep without further purification. ESI MS m/z 307.9, 309.9 [M+H]⁺.

Step E:4-(7-benzyl-2-chloro-6-methyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate

To a mixture of7-benzyl-2,4-dichloro-6-methyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine(2.50 g, 8.11 mmol, 1.00 eq) and tert-butyl piperazine-1-carboxylate(1.54 g, 8.27 mmol, 1.02 eq) in dioxane (50.0 mL) was added DIEA (3.14g, 24.3 mmol, 4.25 mL, 3.00 eq). The mixture was stirred at 60° C. for20 hours. The mixture was concentrated under vacuum. The residue wasdiluted with water (20 mL) and extracted with DCM (2×80 mL). The organiclayers were dried over Na₂SO₄ and concentrated under vacuum. The residuewas purified by automated flash chromatography system (diethylether/ethyl acetate 50:1 to 2:1) to give tert-butyl4-(7-benzyl-2-chloro-6-methyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(2.59 g, 5.29 mmol, 65.2% yield, 93.5% purity) as a yellow solid.

Step F: tert-butyl4-[7-benzyl-2-[2-(dimethylamino)ethoxy]-6-methyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate

To a solution of 2-(dimethylamino)ethanol (701 mg, 7.86 mmol, 788 μL,3.00 eq) in THE (45.0 mL) was added NaH (210 mg, 5.24 mmol, 60.0%purity, 2.00 eq) at 15° C. under N₂. After stirring at 15° C. for 0.5hour, tert-butyl4-(7-benzyl-2-chloro-6-methyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(1.20 g, 2.62 mmol, 1.00 eq) was added. The mixture was stirred at 110°C. for 18 hours in a sealed tube. The mixture was concentrated undervacuum. The residue was purified by column chromatography overAl₂O₃(DCM/MeOH 100:1 to 10:1) to give tert-butyl4-[7-benzyl-2-[2-(dimethylamino)ethoxy]-6-methyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(1.38 g, 2.36 mmol, 90.3% yield, 87.5% purity) as a yellow oil. ESI MSm/z 511.3 [M+H]⁺.

Step G: tert-butyl4-[2-[2-(dimethylamino)ethoxy]-6-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate

To a solution of tert-butyl4-[7-benzyl-2-[2-(dimethylamino)ethoxy]-6-methyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(1.50 g, 2.94 mmol, 1.00 eq) in MeOH (80.0 mL) was added Pd/C (450 mg)under N₂. The suspension was degassed under vacuum and purged withhydrogen 4 times. The mixture was stirred under hydrogen (50 psi) at 40°C. for 12 hours. The reaction mixture was filtered and the filtrate wasconcentrated. The residue was purified by column chromatography(DCM/MeOH 40/1 to 10/1) to give tert-butyl4-[2-[2-(dimethylamino)ethoxy]-6-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(1.15 g, 2.46 mmol, 83.7% yield, 90.0% purity) as a yellow oil.

Step H: tert-butyl4-[7-(3-benzyloxy-1-naphthyl)-2-[2-(dimethylamino)ethoxy]-6-methyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate

Pd₂(dba)₃ (109 mg, 119 μmol, 0.10 eq) was added to a solution oftert-butyl4-[2-[2-(dimethylamino)ethoxy]-6-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(500 mg, 1.19 mmol, 1.00 eq), 3-benzyloxy-1-bromo-naphthalene (410 mg,1.31 mmol, 1.10 eq), 2-dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl(RuPhos) (111 mg, 238 μmol, 0.20 eq) and Cs₂CO₃ (1.16 g, 3.57 mmol, 3.00eq) in dioxane (10.0 mL). The reaction mixture was stirred at 90° C. for12 hours under N₂. The mixture was concentrated under vacuum. Theresidue was diluted with water (5 mL) and extracted with DCM (2×20 mL).The combined organic layers were dried over Na₂SO₄, filtered andconcentrated under vacuum. The residue was purified by columnchromatography over Al₂O₃(DCM/MeOH 100/1 to 10/1) and by preparative TLC(DCM/MeOH 5:1) to give tert-butyl4-[7-(3-benzyloxy-1-naphthyl)-2-[2-(dimethylamino)ethoxy]-6-methyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(309 mg, 453 μmol, 38.1% yield, 95.8% purity) as a yellow oil.

Step I: Tert-butyl4-[2-[2-(dimethylamino)ethoxy]-7-(3-hydroxy-1-naphthyl)-6-methyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate

To a solution of tert-butyl4-[7-(3-benzyloxy-1-naphthyl)-2-[2-(dimethylamino)ethoxy]-6-methyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(340 mg, 521 μmol, 1.00 eq) in MeOH (6.80 mL) was added Pd/C (120 mg)under N₂. The suspension was degassed under vacuum and purged withhydrogen 4 times. The mixture was stirred under hydrogen (15 psi) at 40°C. for 1.5 hours. The mixture was concentrated under vacuum to givetert-butyl4-[2-[2-(dimethylamino)ethoxy]-7-(3-hydroxy-1-naphthyl)-6-methyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(210 mg, 312 μmol, 59.8% yield, 83.5% purity) as a pink solid which wasused directly in the next step without further purification. ESI MS m/z563.3 [M+H]⁺.

Step J:4-[2-[2-(dimethylamino)ethoxy]-6-methyl-4-piperazin-1-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl]naphthalen-2-oltrifluoroacetate

To a solution of tert-butyl4-[2-[2-(dimethylamino)ethoxy]-7-(3-hydroxy-1-naphthyl)-6-methyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(180 mg, 320 μmol, 1.00 eq) in DCM (240 μL) was added TFA (365 mg, 3.20mmol, 237 μL, 10.0 eq). The mixture was stirred at 18° C. for 0.5 hour.The mixture was concentrated under vacuum to give4-[2-[2-(dimethylamino)ethoxy]-6-methyl-4-piperazin-1-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl]naphthalen-2-oltrifluoroacetate (273 mg) as a yellow oil which was used directly in thenext step without further purification.

Step K:1-[4-[2-[2-(dimethylamino)ethoxy]-7-(3-hydroxy-1-naphthyl)-6-methyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one

To a solution of4-[2-[2-(dimethylamino)ethoxy]-6-methyl-4-piperazin-1-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl]naphthalen-2-oltrifluoroacetate (148 mg, 320 μmol, 1.00 eq) and DIEA (494 mg, 3.83mmol, 668 μL, 12.0 eq) in DCM (500 μL) was added prop-2-enoylprop-2-enoate (32.3 mg, 256 μmol, 0.80 eq) dropwise at −50° C. Themixture was stirred at −40 to −20° C. for 30 minutes. The reaction wasquenched with MeOH (20.5 mg) and concentrated under vacuum. The residuewas purified by preparative HPLC (column: Phenomenex Synergi C18150*25*, 10μ; mobile phase: [water (0.1% TFA)-ACN]; B %: 8%-38%, 13 min)to give1-[4-[2-[2-(dimethylamino)ethoxy]-7-(3-hydroxy-1-naphthyl)-6-methyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-onetrifluoroacetate (73.7 mg, 113 μmol, 35.2% yield, 96.3% purity) as ayellow solid. ESI MS m/z 517.3 [M+H]⁺.

Example 49

1-(4-(2-(2-(3-fluoropyrrolidin-1-yl)ethoxy)-7-(3-hydroxynaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-oneStep A:Tert-butyl4-(4-benzyloxycarbonylpiperazin-1-yl)-2-[2-(3-fluoropyrrolidin-1-yl)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate

A mixture of 2-(3-fluoropyrrolidin-1-yl)ethanol (401 mg, 3.01 mmol, 1.60eq), tert-butyl4-(4-benzyloxycarbonylpiperazin-1-yl)-2-methylsulfonyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate(1.00 g, 1.88 mmol, 1.00 eq), Cs₂CO₃ (1.84 g, 5.64 mmol, 3.00 eq),Pd(OAc)₂ (42.2 mg, 188 μmol, 0.10 eq) and BINAP (234 mg, 376 μmol, 0.20eq) in toluene (50.00 mL) was stirred at 110° C. for 3 hours. Themixture was concentrated under vacuum. The residue was purified bycolumn chromatography over silica gel (petroleum ether/ethyl acetate10:1 to 100:1). The desired fractions were collected and concentratedunder vacuum to give tert-butyl4-(4-benzyloxycarbonylpiperazin-1-yl)-2-[2-(3-fluoropyrrolidin-1-yl)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate(1.20 g, 1.07 mmol, 56.8% yield, 52% purity) as a yellow solid. ESI MSm/z 585.3 [M+H]⁺.

Step B: benzyl4-[2-[2-(3-fluoropyrrolidin-1-yl)ethoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate

To a solution of tert-butyl4-(4-benzyloxycarbonylpiperazin-1-yl)-2-[2-(3-fluoropyrrolidin-1-yl)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate(1.20 g, 2.05 mmol, 1.00 eq) in DCM (10.00 mL) was added TFA (3.51 g,30.8 mmol, 2.28 mL, 15.00 eq) at 0° C. The mixture was warmed to 25° C.and stirred for 16 hours. The mixture was diluted with water (100 mL)and the solution was extracted with ethyl acetate (2×100 mL). The waterlayer was basified with saturated aqueous sodium carbonate solution (50mL) and then extracted with ethyl acetate (2×100 mL). The combinedorganic layers were washed with brine (1×100 mL), dried over sodiumsulfate, and filtered. The filtrate was concentrated under vacuum toprovide benzyl4-[2-[2-(3-fluoropyrrolidin-1-yl)ethoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate (800 mg, 1.65 mmol, 80.4%yield) as a yellow gum. ESI MS m/z 485.3 [M+H]⁺.

Step C: benzyl4-[2-[2-(3-fluoropyrrolidin-1-yl)ethoxy]-7-(3-methoxy-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate

A mixture of benzyl4-[2-[2-(3-fluoropyrrolidin-1-yl)ethoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(750 mg, 1.55 mmol, 1.00 eq), (3-methoxy-1-naphthyl)trifluoromethanesulfonate (949 mg, 3.10 mmol, 2.00 eq),2-dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl (RuPhos) (144.66 mg,310.00 μmol, 0.20 eq), Pd₂(dba)₃ (141.94 mg, 155.00 μmol, 0.10 eq) andCs₂CO₃ (1.52 g, 4.65 mmol, 3.00 eq) in toluene (70.00 mL) was stirred at110° C. for 16 hours. The mixture was concentrated under vacuum and thendiluted with ethyl acetate (100 mL) and water (100 mL). The separatedorganic layer was washed with brine (1×100 mL), dried over sodiumsulfate, filtered and concentrated under vacuum. The residue waspurified by column chromatography over silica gel (petroleum ether/ethylacetate 10:1 to ethyl acetate/methanol 10:1). The desired fractions werecollected and concentrated under vacuum to give benzyl4-[2-[2-(3-fluoropyrrolidin-1-yl)ethoxy]-7-(3-methoxy-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(700 mg, 961 μmol, 62.0% yield, 88% purity) as a brown solid. ESI MS m/z641.3 [M+H]⁺.

Step D:2-[2-(3-fluoropyrrolidin-1-yl)ethoxy]-7-(3-methoxy-1-naphthyl)-4-piperazin-1-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine

A mixture of benzyl4-[2-[2-(3-fluoropyrrolidin-1-yl)ethoxy]-7-(3-methoxy-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(700.00 mg, 1.09 mmol, 1.00 eq) in MeOH was hydrogenated (15 psi) at 40°C. with dry Pd/C (140 mg) as a catalyst for 4 hours. The catalyst wasfiltered through a Celite® pelt and the filtrate was concentrated undervacuum to provide2-[2-(3-fluoropyrrolidin-1-yl)ethoxy]-7-(3-methoxy-1-naphthyl)-4-piperazin-1-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine(500 mg, 987 μmol, 90.6% yield) as a brown solid.

Step E:1-[4-[2-[2-(3-fluoropyrrolidin-1-yl)ethoxy]-7-(3-methoxy-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one

To a mixture of2-[2-(3-fluoropyrrolidin-1-yl)ethoxy]-7-(3-methoxy-1-naphthyl)-4-piperazin-1-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine(500 mg, 987 μmol, 1.00 eq) and DIEA (255 mg, 1.97 mmol, 345 μL, 2.00eq) in dichloromethane (8 mL) was added a solution of prop-2-enoylprop-2-enoate (124 mg, 987 μmol, 1.00 eq) in dichloromethane (2 mL) at−40° C. under nitrogen atmosphere. The mixture was warmed to 25° C. andstirred for 1 hour. The mixture was diluted with water (20 mL) anddichloromethane (30 mL). The separated organic layer was washed withbrine (1×30 mL), dried over magnesium sulfate, filtered and concentratedunder vacuum. The residue was purified by column chromatography oversilica gel (dichloromethane/methanol 100/1 to 10/1). The desiredfractions were collected and concentrated under vacuum to give1-[4-[2-[2-(3-fluoropyrrolidin-1-yl)ethoxy]-7-(3-methoxy-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one(450 mg, 714 μmol, 72.4% yield, 89% purity) as a yellow solid. ESI MSm/z 561.2 [M+H]⁺.

Step F:1-[4-[2-[2-(3-fluoropyrrolidin-1-yl)ethoxy]-7-(3-hydroxy-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one

To a solution of 1-[4-[2-[2-(3-fluoropyrrolidin-1-yl)ethoxy]-7-(3-methoxy-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one(400 mg, 713 μmol, 1.00 eq) in DCM (2.00 mL) was added BBr₃ (1.30 g,5.19 mmol, 500 μL, 7.27 eq) at −70° C. under nitrogen atmosphere. Themixture was warmed to 0° C. and stirred for 1 hour. The mixture wasdiluted with dichloromethane (20 mL), and then quenched with saturatedaqueous sodium bicarbonate solution (20 mL). The separated organic layerwas washed with brine (1×10 mL), dried over sodium sulfate, filtered andconcentrated under vacuum. The residue was purified by preparative HPLC(Phenomenex Synergi C18 150*25*, 10μ; mobile phase: [water (0.1%TFA)-ACN]; B %: 18%-48%, 12 min.) The desired fractions were collectedand lyophilized to give1-[4-[2-[2-(3-fluoropyrrolidin-1-yl)ethoxy]-7-(3-hydroxy-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one(40.0 mg, 63.7 μmol, 8.92% yield, 87% purity) was a yellow solid. ESI MSm/z 547.3 [M+H]⁺.

Example 50

1-(4-(2-(2-(dimethylamino)ethoxy)-7-(3-hydroxynaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2-(hydroxymethyl)piperazin-1-yl)prop-2-en-1-oneStep A: 1-tert-butyl2-methyl4-(7-benzyl-2-chloro-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl)piperazine-1,2-dicarboxylate

To a solution of 7-benzyl-2,4-dichloro-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine (2.00 g, 6.80 mmol, 1.00 eq) in DMSO (40.0 mL) was added DIEA(1.76 g, 13.6 mmol, 2.38 mL, 2.00 eq) and 1-tert-butyl2-methylpiperazine-1,2-dicarboxylate (1.74 g, 7.14 mmol, 1.05 eq). Themixture was stirred at 55° C. for 16 hours. The mixture was diluted withwater (100 mL) and extracted with ethyl acetate (3×100 mL). The combinedorganic layers were washed with brine (3×100 mL), dried over Na₂SO₄,filtered and concentrated to dryness. The residue was purified by columnchromatography (SiO₂, diethyl ether/ethyl acetate=1:0 to 3:1) to give1-tert-butyl2-methyl-4-(7-benzyl-2-chloro-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl)piperazine-1,2-dicarboxylate(3.10 g, 5.70 mmol, 83.8% yield, 92.3% purity) as a yellow semisolid.ESI MS m/z 502.2 [M+H]⁺.

Step B: 1-tert-butyl2-methyl4-[7-benzyl-2-[2-(dimethylamino)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1,2-dicarboxylate

A mixture of 1-tert-butyl2-methyl-4-(7-benzyl-2-chloro-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl)piperazine-1,2-dicarboxylate(3.00 g, 5.98 mmol, 1.00 eq), 2-(dimethylamino)ethanol (1.07 g, 12.0mmol, 1.20 mL, 2.00 eq), Cs₂CO₃ (4.87 g, 15.0 mmol, 2.50 eq), Pd(OAc)₂(201 mg, 897 μmol, 0.15 eq) and BINAP (744 mg, 1.20 mmol, 0.20 eq) intoluene (60.0 mL) was degassed and purged with nitrogen 3 times, andthen the mixture was stirred at 110° C. for 3 hours under a nitrogenatmosphere. The reaction mixture was diluted with water (50 mL) andextracted with ethyl acetate (3×50 mL). The combined organic layers werewashed with brine (3×50 mL), dried over Na₂SO₄, filtered andconcentrated to dryness. The residue was purified by columnchromatography (SiO₂, DCM/MeOH=1:0 to 5:1) to give 1-tert-butyl2-methyl-4-[7-benzyl-2-[2-(dimethylamino)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1,2-dicarboxylate (3.10 g, 4.45 mmol, 80.4%yield, 86.0% purity) as a black oil. ESI MS m/z 555.3 [M+H]⁺.

Step C: 1-tert-butyl2-methyl4-[2-[2-(dimethylamino)ethoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1,2-dicarboxylate

To a solution of 1-tert-butyl 2-methyl-4-[7-benzyl-2-[2-(dimethylamino)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1,2-dicarboxylate(2.33 g, 4.20 mmol, 1.00 eq) in MeOH (50.0 mL) was added Pd/C (233 mg)under N₂. The suspension was degassed under vacuum and purged withhydrogen several times. The mixture was stirred under hydrogen (50 psi)at 40° C. for 36 hours. The reaction mixture was filtered and theorganic phase was concentrated to dryness to give1-tert-butyl-2-methyl4-[2-[2-(dimethylamino)ethoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1,2-dicarboxylate(1.50 g, crude) as a colorless oil, which was used directly in the nextstep without further purification.

Step D: 1-tert-butyl2-methyl4-[7-(3-benzyloxy-1-naphthyl)-2-[2-(dimethylamino)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1,2-dicarboxylate

A mixture of1-tert-butyl-2-methyl4-[2-[2-(dimethylamino)ethoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1,2-dicarboxylate(1.50 g, crude), 3-benzyloxy-1-bromo-naphthalene (1.49 g, 4.76 mmol,1.30 eq), Cs₂CO₃ (2.98 g, 9.15 mmol, 2.50 eq), Pd₂(dba)₃ (503 mg, 549μmol, 0.15 eq) and 2-dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl(RuPhos) (342 mg, 732 μmol, 0.20 eq) in dioxane (100 mL) was degassedand purged with nitrogen 3 times, and the mixture was stirred at 85° C.for 5 hours under a nitrogen atmosphere. The reaction mixture wasquenched by adding water (50 mL) at 0° C., and extracted with DCM (3×100mL). The combined organic layers were washed with brine (3×150 mL),dried over Na₂SO₄, filtered and concentrated under reduced pressure todryness. The residue was purified by column chromatography (SiO₂,DCM/MeOH=10:1 to 5:1) to give 1-tert-butyl2-methyl4-[7-(3-benzyloxy-1-naphthyl)-2-[2-(dimethylamino)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1,2-dicarboxylate(1.72 g, 2.25 mmol, 53.5% yield, 91% purity) as a yellow. ESI MS m/z697.3 [M+H]⁺.

Step E: methyl4-[7-(3-benzyloxy-1-naphthyl)-2-[2-(dimethylamino)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-2-carboxylate

To a solution of 1-tert-butyl2-methyl4-[7-(3-benzyloxy-1-naphthyl)-2-[2-(dimethylamino)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1,2-dicarboxylate(1.32 g, 1.89 mmol, 1.00 eq) in DCM (20.0 mL) was added TFA (4.31 g,37.8 mmol, 2.80 mL, 20.0 eq) at 0° C. and the reaction mixture wasstirred for 2 hours at 25° C. The reaction mixture was concentratedunder reduced pressure to dryness. The residue was dissolved in DCM (50mL) and H₂O (20 mL) and the reaction mixture was adjusted to pH 8 withsaturated NaHC03. The organic layer was dried over Na₂SO₄, filtered andconcentrated under reduced pressure to give methyl4-[7-(3-benzyloxy-1-naphthyl)-2-[2-(dimethylamino)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-2-carboxylate(1.12 g, 1.87 mmol, 69.6% yield, 70% purity) as a brown oil, which wasused directly in the next step without further purification. ESI MS m/z597.4 [M+H]⁺.

Step F:[4-[7-(3-benzyloxy-1-naphthyl)-2-[2-(dimethylamino)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]methanol

A mixture of methyl-4-[7-(3-benzyloxy-1-naphthyl)-2-[2-(dimethylamino)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-2-carboxylate(400 mg, 0.670 mmol) in THF (5.00 mL) was added LiAlH₄ (102 mg, 2.68mmol, 4.00 eq) at 0° C. The reaction mixture was degassed and purgedwith nitrogen 3 times, and stirred at 0° C. for 2 hours under a nitrogenatmosphere. The reaction mixture was quenched by addition ofNa₂SO₄.10H₂O (0.5 g) at 0° C., and then diluted with DCM (50 mL). Thecombined organic layers were filtered, dried over Na₂SO₄, andconcentrated under reduced pressure to give[4-[7-(3-benzyloxy-1-naphthyl)-2-[2-(dimethylamino)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]methanol(280 mg, 0.493 mmol, 73.6% yield) as a yellow semisolid, which was useddirectly in the next step without further purification. ESI MS m/z 569.3[M+H]⁺.

Step G:2-[[7-(3-benzyloxy-1-naphthyl)-4-[3-[[tert-butyl(dimethyl)silyl]oxymethyl]piperazin-1-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-2-yl]oxy]-N,N-dimethyl-ethanamine

To a stirred solution of [4-[7-(3-benzyloxy-1-naphthyl)-2-[2-(dimethylamino)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]methanol(250 mg, 440 μmol, 1.00 eq) and NaH (176 mg, 4.40 mmol, 60.0% purity,10.0 eq) in THE (10.0 mL) was added tert-butyldimethylsilyl chloride(232 mg, 1.54 mmol, 189 μL, 3.50 eq) at 0° C. The mixture was stirred at25° C. for 12 hours under a nitrogen atmosphere. The reaction mixturewas quenched by addition of water (25 mL) at 0° C. and extracted withDCM (3×30 mL). The combined organic layers were washed with brine (3×30mL), dried over Na₂SO₄, filtered and concentrated under reduced pressureto dryness. The residue was purified by preparative TLC (SiO₂,DCM/MeOH=10:1) to give2-[[7-(3-benzyloxy-1-naphthyl)-4-[3-[[tert-butyl(dimethyl)silyl]oxymethyl]piperazin-1-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-2-yl]oxy]-N,N-dimethyl-ethanamine(128 mg, 180 μmol, 40.9% yield, 96.0% purity) as a colorless semisolid.ESI MS m/z 683.3 [M+H]⁺.

Step H: 1-[4-[7-(3-benzyloxy-1-naphthyl)-2-[2-(dimethylamino)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-[[tert-butyl(dimethyl)silyl]oxymethyl]piperazin-1-yl]prop-2-en-1-one

To a solution of 2-[[7-(3-benzyloxy-1-naphthyl)-4-[3-[[tert-butyl(dimethyl)silyl]oxymethyl]piperazin-1-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-2-yl]oxy]-N,N-dimethyl-ethanamine(128 mg, 187 μmol, 1.00 eq) and triethylamine (47.4 mg, 469 μmol, 65.0μL, 2.50 eq) in DCM (5.00 mL) was added prop-2-enoyl prop-2-enoate (35.5mg, 281 μmol, 1.50 eq) dropwise at −40° C. and stirred for 30 minutes.The reaction mixture was concentrated under reduced pressure to dryness.The residue was purified by preparative TLC (SiO₂, DCM/MeOH=10:1) togive 1-[4-[7-(3-benzyloxy-1-naphthyl)-2-[2-(dimethylamino)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-[[tert-butyl(dimethyl)silyl]oxymethyl]piperazin-1-yl]prop-2-en-1-one(92.0 mg, 101 μmol, 54.0% yield, 81.0% purity) as a yellow solid. ESI MSm/z 737.3 [M+H]⁺.

Step I:1-[4-[2-[2-(dimethylamino)ethoxy]-7-(3-hydroxy-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(hydroxymethyl)piperazin-1-yl]prop-2-en-1-one

A mixture of 1-[4-[7-(3-benzyloxy-1-naphthyl)-2-[2-(dimethylamino)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-[[tert-butyl(dimethyl)silyl]oxymethyl]piperazin-1-yl]prop-2-en-1-one(92.0 mg, 125 μmol, 1.00 eq) in DCM (8.00 mL) was added BBr₃ (17.0 mg,67.8 μmol, 6.53 μL, 10.0 eq). The mixture was stirred at −40° C. for 30minutes under a nitrogen atmosphere and then concentrated at 25° C.under reduced pressure to dryness. To the residue was added saturatedNaHCO₃ aqueous (0.5 mL). The solution was adjusted to pH 7 at 0° C. andthen MeOH (2.0 mL) was added. The solution was purified by preparativeHPLC (column: Phenomenex Synergi C18 150*25*, 10μ; mobile phase: [water(0.1% TFA)-ACN]; B %: 15%-45%, 11 min). The desired fractions werecollected and concentrated under reduced pressure to remove MeCN andlyophilized to give1-[4-[2-[2-(dimethylamino)ethoxy]-7-(3-hydroxy-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(hydroxymethyl)piperazin-1-yl]prop-2-en-1-one(6.30 mg, 11.2 μmol, 9.00% yield, 95.0% purity) as a yellow solid. ESIMS m/z 533.2 [M+H]⁺.

Example 51

1-acryloyl-4-(2-(2-(dimethylamino)ethoxy)-7-(3-hydroxynaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-N,N-dimethylpiperazine-2-carboxamideStep A:4-[7-(3-benzyloxy-1-naphthyl)-2-[2-(dimethylamino)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-tert-butoxycarbonyl-piperazine-2-carboxylicAcid

To a solution of 1-tert-butyl 2-methyl4-[7-(3-benzyloxy-1-naphthyl)-2-[2-(dimethylamino)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1,2-dicarboxylate(300 mg, 431 μmol, 1.00 eq) in THE (4.00 mL) and H2O (1.00 mL) was addedNaOH (68.9 mg, 1.72 mmol, 4.00 eq). The mixture was stirred at 25° C.for 12 hours under a nitrogen atmosphere. The reaction mixture wasdiluted with water (50 mL) and the reaction mixture was adjusted to pH 6with HCl (6 M) and then extracted with DCM (3×50 mL). The combinedorganic layers were dried over Na₂SO₄, filtered and concentrated underreduced pressure to dryness to give4-[7-(3-benzyloxy-1-naphthyl)-2-[2-(dimethylamino)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-tert-butoxycarbonyl-piperazine-2-carboxylicacid (310 mg, crude) as a yellow solid which was used directly in thenext step without further purification. ESI MS m/z 683.3 [M+H]⁺.

Step B:tert-butyl4-[7-(3-benzyloxy-1-naphthyl)-2-[2-(dimethylamino)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(dimethylcarbamoyl)piperazine-1-carboxylate

A mixture of4-[7-(3-benzyloxy-1-naphthyl)-2-[2-(dimethylamino)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-tert-butoxycarbonyl-piperazine-2-carboxylicacid (310 mg, crude) and DIEA (352 mg, 2.72 mmol, 476 μL) in DCM (10.0mL) was added portionwise HATU (259 mg, 681 μmol) at 0° C. Afterstirring for 30 minutes, N-methylmethanamine (130 mg, 1.59 mmol, 146 μL,HCl) was added in one portion. The reaction mixture was degassed andpurged with nitrogen 3 times. After stirring at 25° C. for 12 hoursunder a nitrogen atmosphere, the reaction mixture was diluted with water(50 mL) at 0° C. and extracted with DCM (3×50 mL). The combined organiclayers were adjusted to pH 6 with HCl (1 M), washed with brine (3×50 mL)and water (3×50 mL), dried over Na₂SO₄, filtered and concentrated underreduced pressure to dryness to givetert-butyl4-[7-(3-benzyloxy-1-naphthyl)-2-[2-(dimethylamino)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(dimethylcarbamoyl)piperazine-1-carboxylate(345 mg, 428 μmol, two steps 94.2% yield, 88.0% purity) as a yellowsemi-solid. ESI MS m/z 710.3 [M+H]⁺.

Step C: Tert-butyl4-[2-[2-(dimethylamino)ethoxy]-7-(3-hydroxy-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(dimethylcarbamoyl)piperazine-1-carboxylate

To a solution of tert-butyl4-[7-(3-benzyloxy-1-naphthyl)-2-[2-(dimethylamino)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(dimethylcarbamoyl)piperazine-1-carboxylate(345 mg, 486 μmol, 1.00 eq) in MeOH (5.00 mL) was added Pd/C (80.0 mg)under N₂. The suspension was degassed under vacuum and purged withhydrogen several times. The mixture was stirred under hydrogen (15 psi)at 25° C. for 8 hours. The reaction mixture was filtered and thefiltrate was concentrated under reduced pressure to dryness to givetert-butyl4-[2-[2-(dimethylamino)ethoxy]-7-(3-hydroxy-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(dimethylcarbamoyl)piperazine-1-carboxylate(197 mg, crude) as a brown solid, which was used directly in the nextstep without further purification. ESI MS m/z 620.3 [M+H]⁺.

Step D:4-[2-[2-(dimethylamino)ethoxy]-7-(3-hydroxy-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-N,N-dimethyl-piperazine-2-carboxamide

A mixture of tert-butyl4-[2-[2-(dimethylamino)ethoxy]-7-(3-hydroxy-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(dimethylcarbamoyl)piperazine-1-carboxylate(197 mg, crude) in DCM (5.00 mL) was added HCl/dioxane (4 M, 1.61 mL) at0° C. The reaction mixture was degassed and purged with nitrogen 3 timesand stirred at 25° C. for 2 hours under a nitrogen atmosphere. Thereaction mixture was concentrated under reduced pressure to dryness. Theresidue was purified by preparative HPLC (column: Phenomenex Synergi C18150*25*, 10μ; mobile phase: [water (0.05% HCl)-ACN]; B %: 10%-30%, 7.8min). The collected water phase was lyophilized to dryness to give4-[2-[2-(dimethylamino)ethoxy]-7-(3-hydroxy-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-N,N-dimethyl-piperazine-2-carboxamide(90.0 mg, 171 μmol, 53.1% yield, 99.0% purity) as a brown solid. ESI MSm/z 520.2 [M+H]⁺.

Step E:4-[2-[2-(dimethylamino)ethoxy]-7-(3-hydroxy-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-N,N-dimethyl-1-prop-2-enoyl-piperazine-2-carboxamide

To a solution of4-[2-[2-(dimethylamino)ethoxy]-7-(3-hydroxy-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-N,N-dimethyl-piperazine-2-carboxamide(70.0 mg, 135 μmol, 1.00 eq) in DMAC (500 μL) was added triethylamine(40.9 mg, 404 μmol, 56.0 μL, 3.00 eq) at 0° C. and then prop-2-enoylprop-2-enoate (2.55 mg, 20.2 μmol, 0.15 eq) was added. The mixture wasstirred at 0° C. for 2 hours under a nitrogen atmosphere. The reactionmixture was filtered and the collected organic phase was purified bypreparative HPLC (column: Phenomenex Synergi C18 150*25*, 10μ; mobilephase: [water (0.1% TFA)-ACN]; B %: 15%-45%, 12 min). The collectedwater phase was lyophilized to give4-[2-[2-(dimethylamino)ethoxy]-7-(3-hydroxy-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-N,N-dimethyl-1-prop-2-enoyl-piperazine-2-carboxamide(10.0 mg, 16.5 μmol, 12.2% yield, 94.6% purity) as a yellow semisolid.ESI MS m/z 574.2 [M+H]⁺.

Example 52

1-[4-[7-(3-hydroxy-1-naphthyl)-2-[2-(1-piperidyl)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-oneStep A: tert-butyl4-[7-benzyl-2-[2-(1-piperidyl)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate

To a solution of 2-(1-piperidyl)ethanol (872 mg, 6.75 mmol, 899 μL, 3.00eq) in toluene (40.0 mL) was added Pd(OAc)₂ (50.5 mg, 225 μmol, 0.10eq), Cs₂CO₃ (2.20 g, 6.75 mmol, 3.00 eq), BINAP (280 mg, 450 μmol, 0.20eq) and tert-butyl4-(7-benzyl-2-chloro-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(1.00 g, 2.25 mmol, 1.00 eq). The mixture was stirred at 110° C. for 12hours under N₂ and then concentrated under vacuum. The residue wasdiluted with water (10.0 mL), extracted with ethyl acetate (3×20 mL),washed with brine (1×50 mL), dried over Na₂SO₄, filtered andconcentrated under vacuum. The residue was purified by columnchromatography (SiO₂, DCM/MeOH=10:1) to give tert-butyl4-[7-benzyl-2-[2-(1-piperidyl)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(700 mg, 1.30 mmol, 58.0% yield) as a red solid. ESI MS m/z 537.3[M+H]⁺.

Step B: tert-butyl4-[2-[2-(1-piperidyl)ethoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate

To a mixture of tert-butyl4-[7-benzyl-2-[2-(1-piperidyl)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(600 mg, 1.12 mmol, 1.00 eq) in MeOH (50.0 mL) was added Pd/C (67.2 mg,10%). The mixture was stirred at 40° C. for 24 hours at 50 psi under H₂.The mixture was filtered and concentrated under vacuum to givetert-butyl4-[2-[2-(1-piperidyl)ethoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate (500 mg, crude) as a brown oil and used in thenext step without further purification. ESI MS m/z 447.3 [M+H]⁺.

Step C: tert-butyl4-[7-(3-methoxy-1-naphthyl)-2-[2-(1-piperidyl)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate

To a solution of tert-butyl4-[2-[2-(1-piperidyl)ethoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(250 mg) and (3-methoxy-1-naphthyl) trifluoromethanesulfonate (343 mg,1.12 mmol) in toluene (6.00 mL) was added2-dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl (RuPhos) (52.3 mg,112 μmol), Pd₂(dba)₃ (32.19 mg, 55.98 μmol) and Cs₂CO₃ (548 mg, 1.68mmol). After stirring at 110° C. for 72 hours under N₂, the mixture wasconcentrated under vacuum, diluted with water (20.0 mL), extracted withethyl acetate (3×30.0 mL), washed with brine (1×50.0 mL), dried overNa₂SO₄, filtered and concentrated under vacuum. The residue was purifiedby column chromatography (SiO₂, DCM/MeOH=10:1) to give tert-butyl4-[7-(3-methoxy-1-naphthyl)-2-[2-(1-piperidyl)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate (140 mg, 232 μmoL, twosteps, 41.5% yield) as a yellow solid. ESI MS m/z 603.3 [M+H]⁺.

Step D:7-(3-methoxy-1-naphthyl)-4-piperazin-1-yl-2-[2-(1-piperidyl)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine

A mixture of tert-butyl 4-[7-(3-methoxy-1-naphthyl)-2-[2-(1-piperidyl)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(120 mg, 199 μmol, 1.00 eq) and TFA (340 mg, 2.99 mmol, 221 μL, 15.0 eq)in DCM (1.00 mL) was stirred at 25° C. for 1 hour. The mixture wasconcentrated under vacuum to give7-(3-methoxy-1-naphthyl)-4-piperazin-1-yl-2-[2-(1-piperidyl)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidinebis-trifluoroacetate (145 mg, crude) as a yellow solid which was usedinto next step without further purification. ESI MS m/z 503.3 [M+H]⁺.

Step E: 1-[4-[7-(3-methoxy-1-naphthyl)-2-[2-(1-piperidyl)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one

To a solution of7-(3-methoxy-1-naphthyl)-4-piperazin-1-yl-2-[2-(1-piperidyl)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidinebis-trifluoroacetate (145 mg, crude) and Et₃N (221 mg, 2.18 mmol, 303μL) in DCM (2.00 mL) was added prop-2-enoyl prop-2-enoate (25.0 mg, 198μmol) at −78° C. After stirring at 0° C. for 0.5 h, the mixture quenchedwith MeOH and concentrated under vacuum. The mixture was purified bycolumn chromatography (SiO₂, DCM/MeOH=10:1) to give1-[4-[7-(3-methoxy-1-naphthyl)-2-[2-(1-piperidyl)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one(90.0 mg, 162 μmol, two steps 81.5% yield) a yellow solid. ESI MS m/z557.3 [M+H]⁺.

Step F:1-[4-[7-(3-hydroxy-1-naphthyl)-2-[2-(1-piperidyl)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one

To a solution of 1-[4-[7-(3-methoxy-1-naphthyl)-2-[2-(1-piperidyl)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one(90.0 mg, 162 μmol, 1.00 eq) in DCM (2.00 mL) was added BBr₃ (405 mg,1.62 mmol, 156 μL, 10.0 eq) at −78° C. After stirring at 0° C. for 1 h,the mixture was quenched with saturated sodium bicarbonate solution at−78° C. and stirred at 0° C. for 0.5 h. The mixture was extracted withethyl acetate (3×20.0 mL), washed with brine (1×40.0 mL), dried overNa₂SO₄, filtered and concentrated under vacuum. The residue was purifiedby preparative HPLC (Phenomenex Gemini 150*25 mm*, 10μ; mobile phase:[water (0.05% ammonia hydroxide v/v)-ACN]; B %: 55%-85%, 10 min) to give1-[4-[7-(3-hydroxy-1-naphthyl)-2-[2-(1-piperidyl)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one(6.19 mg, 10.8 μmol, 6.71% yield, 95% purity) as a yellow oil. ESI MSm/z 543.2 [M+H]⁺.

Example 53

1-(4-(2-(2-(dimethylamino)ethoxy)-7-(3-hydroxynaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-3-(hydroxymethyl)piperazin-1-yl)prop-2-en-1-oneStep A: 1-tert-butyl 3-methyl4-(7-benzyl-2-chloro-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1,3-dicarboxylate

A mixture of 7-benzyl-2,4-dichloro-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine (3.00 g, 10.2 mmol, 1.00 eq), 1-tert-butyl-3-methylpiperazine-1,3-dicarboxylate (2.62 g, 10.7 mmol, 1.05 eq), DIEA (3.30 g,25.5 mmol, 4.45 mL, 2.50 eq) in DMSO (50.0 mL) was degassed and purgedwith nitrogen 3 times. The mixture was stirred at 100° C. for 12 hoursunder a nitrogen atmosphere. The reaction mixture was diluted with DCM(200 mL), washed with brine (3×50 mL), dried over Na₂SO₄, filtered andconcentrated under reduced pressure to dryness. The residue was purifiedby column chromatography (SiO₂, Petroleum ether/Ethyl acetate=10:1 to3:1) to give 1-tert-butyl 3-methyl4-(7-benzyl-2-chloro-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1,3-dicarboxylate(2.10 g, 3.81 mmol, 37.4% yield, 91.0% purity) as a yellow oil. ESI MSm/z 502.1 [M+H]⁺.

Step B: 1-tert-butyl3-methyl4-(7-benzyl-2-(2-(dimethylamino)ethoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1,3-dicarboxylate

A mixture of 1-tert-butyl 3-methyl4-(7-benzyl-2-chloro-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1,3-dicarboxylate(2.10 g, 4.17 mmol, 1.00 eq), 2-(dimethylamino)ethanol (929 mg, 10.4mmol, 1.04 mL, 2.50 eq), Pd(OAc)₂ (140 mg, 625 μmol, 0.15 eq), BINAP(519 mg, 833 μmol, 0.20 eq) and Cs₂CO₃ (3.39 g, 10.4 mmol, 2.50 eq) intoluene (60.0 mL) was degassed and purged with nitrogen for 3 times. Themixture was stirred at 110° C. for 3 hours under a nitrogen atmosphere.The reaction mixture was filtered and concentrated under reducedpressure to dryness. The residue was purified by column chromatography(SiO₂, DCM/MeOH=30:1 to 10:1) to give 1-tert-butyl3-methyl4-(7-benzyl-2-(2-(dimethylamino)ethoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1,3-dicarboxylate(1.30 g, 1.67 mmol, 40.0% yield, 71.4% purity) as a yellow solid. ESI MSm/z 555.3 [M+H]⁺.

Step C: 1-tert-butyl 3-methyl4-(2-(2-(dimethylamino)ethoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1,3-dicarboxylate

To a solution of 1-tert-butyl 3-methyl4-(7-benzyl-2-(2-(dimethylamino)ethoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1,3-dicarboxylate(1.30 g, 2.34 mmol, 1.00 eq) in MeOH (15.0 mL) was added Pd/C (300 mg)under N₂. The suspension was degassed under vacuum and purged withhydrogen several times. The mixture was stirred under hydrogen (50 psi)at 45° C. for 48 hours. The catalyst was filtered off and the filtratewas concentrated under reduced pressure to give 1-tert-butyl 3-methyl4-(2-(2-(dimethylamino)ethoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1,3-dicarboxylate (780 mg, crude) as a colorless oil, whichwas used directly in the next step without further purification.

Step D: 1-tert-butyl 3-methyl4-(7-(3-(benzyloxy)naphthalen-1-yl)-2-(2-(dimethylamino)ethoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1,3-dicarboxylate

A mixture of 1-tert-butyl 3-methyl4-(2-(2-(dimethylamino)ethoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1,3-dicarboxylate(780 mg, crude), 3-benzyloxy-1-bromo-naphthalene (684 mg, 2.18 mmol),Pd₂(dba)₃ (231 mg, 252 μmol), Cs₂CO₃ (1.37 g, 4.20 mmol) and2-dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl (RuPhos) (157 mg, 336μmol) in dioxane (20.0 mL) was degassed and purged with nitrogen 3times. The mixture was stirred at 85° C. for 5 hours under a nitrogenatmosphere. The reaction mixture was filtered and concentrated underreduced pressure to dryness. The residue was purified by columnchromatography (SiO₂, DCM/MeOH=10:1 to 5:1) to give 1-tert-butyl3-methyl4-(7-(3-(benzyloxy)naphthalen-1-yl)-2-(2-(dimethylamino)ethoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1,3-dicarboxylate(750 mg, 1.02 mmol, two steps 43.6% yield, 95.0% purity) as a yellowsolid. ¹H NMR (400 MHz, chloroform-d) 6=8.10 (d, J=8.0 Hz, 1H), 7.73 (d,J=8.0 Hz, 1H), 7.58-7.31 (m, 8H), 7.00 (d, J=2.0 Hz, 1H), 6.89 (d, J=2.0Hz, 1H), 5.18 (s, 2H), 4.75 (br s, 1H), 4.45 (br d, J=13.2 Hz, 1H),4.42-4.34 (m, 1H), 4.34-4.28 (m, 1H), 4.15 (br s., 2H), 4.13-3.91 (m,1H), 3.85-3.70 (m, 5H), 3.49-3.33 (m, 2H), 3.31-3.07 (m, 2H), 2.99 (brs, 1H), 2.83-2.68 (m, 3H), 2.35 (s, 6H), 1.48 (s, 9H).

Step E: methyl1-(7-(3-(benzyloxy)naphthalen-1-yl)-2-(2-(dimethylamino)ethoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-2-carboxylate

To a solution of 1-tert-butyl 3-methyl4-(7-(3-(benzyloxy)naphthalen-1-yl)-2-(2-(dimethylamino)ethoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1,3-dicarboxylate(200 mg, 287 μmol, 1.00 eq) in DCM (5.00 mL) was added TFA (770 mg, 6.75mmol, 500 μL, 23.5 eq) at 0° C. The mixture was stirred at 25° C. for 2hours under a nitrogen atmosphere. The reaction mixture was concentratedunder reduced pressure to dryness. The residue was dissolved in DCM (100mL) and water (50 mL) and the solution was adjusted to pH 8 withsaturated Na₂CO₃ aqueous and then extracted with DCM (3×50 mL). Thecombined organic layers were washed with brine (3×50 mL), dried overNa₂SO₄, filtered and concentrated under reduced pressure to give methyl1-(7-(3-(benzyloxy)naphthalen-1-yl)-2-(2-(dimethylamino)ethoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-2-carboxylate(171 mg, 263 μmol, 91.6% yield, 91.7% purity) as a yellow solid. ESI MSm/z 597.2 [M+H]⁺.

Step F: (1-(7-(3-(benzyloxy)naphthalen-1-yl)-2-(2-(dimethylamino)ethoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)methanol

To a mixture of methyl1-(7-(3-(benzyloxy)naphthalen-1-yl)-2-(2-(dimethylamino)ethoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-2-carboxylate(171 mg, 287 μmol, 1.00 eq) in THE (5.00 mL) was added LiAlH₄ (65.3 mg,1.72 mmol, 6.00 eq) at 0° C. After stirring for 2 hours at 25° C., thereaction mixture was quenched by addition of water (30 mL) at 0° C., andextracted with DCM (3×30 mL). The combined organic layers were washedwith brine (3×30 mL). The collected organic phase was dried over Na₂SO₄,filtered and concentrated under reduced pressure to give(1-(7-(3-(benzyloxy)naphthalen-1-yl)-2-(2-(dimethylamino)ethoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)methanol(160 mg, 281 μmol, 98.2% yield, 100% purity) as a colorless semisolid.ESI MS m/z 569.2 [M+H]⁺.

Step G:2-((7-(3-(benzyloxy)naphthalen-1-yl)-4-(2-(((tert-butyldimethylsilyl)oxy)methyl)piperazin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)oxy)-N,N-dimethylethanamine

To a mixture of (1-(7-(3-(benzyloxy)naphthalen-1-yl)-2-(2-(dimethylamino)ethoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)methanol(160 mg, 281 μmol, 1.00 eq) in THE (5.00 mL) was added NaH (94.0 mg,2.35 mmol, 60.0% purity, 8.00 eq) at 0° C. After stirring for 30minutes, tert-butyldimethylsilyl chloride (133 mg, 881 μmol, 108 μL,3.00 eq) was added dropwise. The mixture was stirred at 25° C. for 6hours under a nitrogen atmosphere. The reaction mixture was concentratedunder reduced pressure to give2-((7-(3-(benzyloxy)naphthalen-1-yl)-4-(2-(((tert-butyldimethylsilyl)oxy)methyl)piperazin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)oxy)-N,N-dimethylethanamine(133 mg, 165 μmol, 56.1% yield, 84.6% purity) as a slight yellow solid,which was used directly in the next step without further purification.ESI MS m/z 683.2 [M+H]⁺.

Step H: 1-(4-(7-(3-(benzyloxy)naphthalene-1-yl)-2-(2-(dimethylamino)ethoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-3-(((tert-butyldimethylsilyl)oxy)methyl)piperazin-1-yl)prop-2-en-1-one

1 To a solution of2-((7-(3-(benzyloxy)naphthalen-1-yl)-4-(2-(((tert-butyldimethylsilyl)oxy)methyl)piperazin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)oxy)-N,N-dimethylethanamine(133 mg, 165 μmol, 1.00 eq) and TEA (39.4 mg, 389 μmol, 54.0 μL, 2.00eq) in DCM (3.00 mL) was added prop-2-enoyl prop-2-enoate (31.9 mg, 253μmol, 1.30 eq) at −40° C. After stirring at −40° C. for 2 hours, thereaction mixture was quenched with MeOH (1 M) and concentrated underreduced pressure to give 1-(4-(7-(3-(benzyloxy)naphthalene-1-yl)-2-(2-(dimethylamino)ethoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-3-(((tert-butyldimethylsilyl)oxy)methyl)piperazin-1-yl)prop-2-en-1-one(140 mg, crude) as a yellow solid. ESI MS m/z 737.2 [M+H]⁺.

Step I:1-(4-(2-(2-(dimethylamino)ethoxy)-7-(3-hydroxynaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-3-(hydroxymethyl)piperazin-1-yl)prop-2-en-1-one

To a solution of1-(4-(7-(3-(benzyloxy)naphthalen-1-yl)-2-(2-(dimethylamino)ethoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-3-(((tert-butyldimethylsilyl)oxy)methyl)piperazin-1-yl)prop-2-en-1-one(140 mg, crude) in DCM (5.00 mL) was added BBr₃ (476 mg, 1.90 mmol, 183μL) at −40° C. After stirring for 2 hours at −40° C. under a nitrogenatmosphere, the mixture was concentrated under reduced pressure todryness. Water (0.5 mL) and MeOH (2.5 mL) were added and the resultingsolution was purified by preparative IPLC (column: Waters Xbridge 150*255u; mobile phase: [water (10 mM NH₄HCO₃)-ACN]; B %: 27%-57%, 11 min).The desired fractions were collected and lyophilized to give1-(4-(2-(2-(dimethylamino)ethoxy)-7-(3-hydroxynaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-3-(hydroxymethyl)piperazin-1-yl)prop-2-en-1-one(4.32 mg, 7.94 μmol, 4.18% yield, 97.9% purity) as a white solid. ESI MSm/z 533.4 [M+H]⁺.

Example 54

1-[4-[7-(3-amino-1-isoquinolyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-oneStep A: tert-butyl 4-hydroxy-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate

To a solution of Na (4.24 g, 184 mmol, 4.37 mL, 2.50 eq) in EtOH (400mL) was added 1-tert-butyl 4-ethyl 3-oxopiperidine-1,4-dicarboxylate(20.0 g, 73.7 mmol, 1.00 eq) and acetic acid methanimidamide (11.5 g,111 mmol, 1.50 eq) under N₂. The mixture was stirred at 70° C. for 5hours. The reaction mixture was adjusted to pH 7 with HCl (1N),extracted with DCM (3×200 mL), washed with brine (1×400 mL), dried overNa₂SO₄, filtered and concentrated under vacuum to give tert-butyl4-hydroxy-6,8-dihydro-5H-pyrido [3,4-d]pyrimidine-7-carboxylate (16.0 g,63.7 mmol, 86.4% yield) as a brown solid. ESI MS m/z 274.0 [M+H]⁺.

Step B: tert-butyl4-(4-benzyloxycarbonylpiperazin-1-yl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate

To a solution of tert-butyl 4-hydroxy-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate (16.0 g, 63.7 mmol, 1.00 eq) in DMF (4.00 mL)was added DBU (29.1 g, 191 mmol, 28.8 mL, 3.00 eq) andbenzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate(PYBOP) (39.8 g, 76.4 mmol, 1.20 eq). The mixture was stirred at 25° C.for 1 hour. Benzyl piperazine-1-carboxylate (21.0 g, 95.5 mmol, 18.5 mL,1.50 eq) was added and the reaction mixture was stirred at 25° C. for 16hours. The mixture was diluted with ethyl acetate (500 mL) and washedwith water (3×400 mL), dried over Na₂SO₄, filtered and concentratedunder vacuum. The residue was purified by column chromatography (SiO₂,diethyl ether/ethyl acetate=1:1) to give tert-butyl4-(4-benzyloxycarbonylpiperazin-1-yl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate(2.00 g, 4.41 mmol, 6.93% yield) as a yellow oil. ESI MS m/z 454.3[M+H]⁺.

Step C

A mixture of tert-butyl4-(4-benzyloxycarbonylpiperazin-1-yl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate(1.20 g, 2.65 mmol, 1.00 eq) and TFA (4.53 g, 39.7 mmol, 2.94 mL, 15.0eq) in DCM (2.00 mL) was stirred at 25° C. for 1 hour. The mixture wasconcentrated under vacuum. The concentrated material was adjusted to pH8 with saturated aq. NaHCO₃, then extracted with ethyl acetate (3×30.0mL), washed with brine (1×100 mL), dried over Na₂SO₄, filtered andconcentrated under vacuum to give benzyl4-(5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate (800 mg, 2.26 mmol, 85.4% yield)as a yellow oil. ESI MS m/z 354.3 [M+H]⁺.

Step D: benzyl4-[7-[3-(tert-butoxycarbonylamino)-1-isoquinolyl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate

A mixture of tert-butyl N-(1-bromo-3-isoquinolyl)carbamate (330 mg, 1.02mmol, 1.00 eq), DIEA (264 mg, 2.04 mmol, 357 μL, 2.00 eq) and benzyl4-(5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(541 mg, 1.53 mmol, 1.50 eq) in DMSO (3.00 mL) was stirred at 80° C. for10 hours. The mixture was diluted with water (5.00 mL) and extractedwith ethyl acetate (3×20 mL). The combined extracts were dried oversodium sulfate, filtered and concentrated under vacuum. The residue waspurified by reverse-phase column (TFA, 0.1%) to give benzyl4-[7-[3-(tert-butoxycarbonylamino)-1-isoquinolyl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(400 mg, 665 μmol, 65.2% yield) as a yellow solid. ESI MS m/z 596.3[M+H]⁺.

Step E: Tert-butylN-[1-(4-piperazin-1-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl)-3-isoquinolyl]carbamate

A mixture of benzyl4-[7-[3-(tert-butoxycarbonylamino)-1-isoquinolyl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(240 mg, 403 μmol, 1.00 eq), KOH (36.2 mg, 645 μmol, 1.60 eq) in H₂O(2.40 mL) and n-butyl alcohol (2.40 mL) was stirred at 100° C. for 12hours. The mixture was diluted with ethyl acetate (3×5.00 mL), washedwith brine (1×10.0 mL), dried over Na₂SO₄, filtered and concentratedunder vacuum to give tert-butylN-[1-(4-piperazin-1-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl)-3-isoquinolyl]carbamate(150 mg, 325 μmol, 80.7% yield) as a yellow oil. ESI MS m/z 462.3[M+H]⁺.

Step F:1-(4-piperazin-1-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl)isoquinolin-3-amineTrifluoroacetate

A solution of tert-butylN-[1-(4-piperazin-1-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl)-3-isoquinolyl]carbamate(150 mg, 325 μmol, 1.00 eq) and TFA (556 mg, 4.87 mmol, 361 μL, 15.0 eq)in DCM (360 μL) was stirred at 25° C. for 1 hours. The mixture wasconcentrated under vacuum to give1-(4-piperazin-1-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl)isoquinolin-3-aminetrifluoroacetate (154.52 mg, crude) as a yellow solid which was usedinto next step without further purification.

Step G:1-[4-[7-(3-amino-1-isoquinolyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one

To a solution of 1-(4-piperazin-1-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl)isoquinolin-3-amine trifluoroacetate (150 mg, crude) andEt3N (319 mg, 3.15 mmol, 437 μL) in DCM (2.00 mL) was added prop-2-enoylprop-2-enoate (31.8 mg, 252 μmol) at −40° C., then stirred at −40° C.for 0.5 h. The mixture was quenched by adding MeOH (20.22 mg, 630.96μmol) and concentrated under vacuum. The residue was purified bypreparative HPLC (Phenomenex Gemini 150*25 mm*, 10μ; mobile phase:[water (0.05% ammonia hydroxide v/v)-ACN]; B %: 26%-56%, 10 min) to give1-[4-[7-(3-amino-1-isoquinolyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one(35.4 mg, 82.5 μmol, 26.2% yield, 96.8% purity) as a yellow solid. ESIMS m/z 416.3 [M+H]⁺.

Example 55

1-(4-(2-(2-(dimethylamino)-3-hydroxypropoxy)-7-(3-hydroxynaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Synthesized according to the method of Example 8, using2-(dimethylamino)propane-1,3-diol in place of(S)-1-(dimethylamino)propan-2-ol in Step B. ES+APCI MS m/z 533.3[M+H]⁺.

Example 56

(R)-1-(4-(7-(3-hydroxynaphthalen-1-yl)-2-((1-morpholinopropan-2-yl)oxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Synthesized according to the method of Example 8, using(R)-1-morpholinopropan-2-ol in place of (S)-1-(dimethylamino)propan-2-olin Step B. ES+APCI MS m/z 559.3 [M+H]⁺.

Example 57

(S)-5-(((4-(4-acryloylpiperazin-1-yl)-7-(3-hydroxynaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)oxy)methyl)pyrrolidin-2-one

Synthesized according to the method of Example 8, using(S)-5-(hydroxymethyl)pyrrolidin-2-one in place of(S)-1-(dimethylamino)propan-2-ol in Step B. ES+APCI MS m/z 529.3 [M+H]⁺.

Example 58

(R)-5-(((4-(4-acryloylpiperazin-1-yl)-7-(3-hydroxynaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)oxy)methyl)pyrrolidin-2-one

Synthesized according to the method of Example 8, using(R)-5-(hydroxymethyl)pyrrolidin-2-one in place of(S)-1-(dimethylamino)propan-2-ol in Step B. ES+APCI MS m/z 529.2 [M+H]⁺.

Example 59

N-(2-((4-(4-acryloylpiperazin-1-yl)-7-(3-hydroxynaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)oxy)ethyl)acetamide

Synthesized according to the method of Example 8, usingN-(2-hydroxyethyl)acetamide in place of (S)-1-(dimethylamino)propan-2-olin Step B. ES+APCI MS m/z 517.3 [M+H]⁺.

Example 60

(R)-1-(4-(2-((1-(dimethylamino)butan-2-yl)oxy)-7-(3-hydroxynaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Synthesized according to the method of Example 8, using(R)-1-(dimethylamino)butan-2-ol in place of(S)-1-(dimethylamino)propan-2-ol in Step B. ES+APCI MS m/z 545.3 [M+H]⁺.

Example 61

(S)-6-(((4-(4-acryloylpiperazin-1-yl)-7-(3-hydroxynaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)oxy)methyl)piperidin-2-one

Synthesized according to the method of Example 8, using6-(hydroxymethyl)piperidin-2-one in place of(S)-1-(dimethylamino)propan-2-ol in Step B and the product was separatedby chiral chromatography. Peak 2 was given the (S) stereochemistry andthis was not confirmed. ES+APCI MS m/z 543.3 [M+H]⁺.

Example 62

(R)-6-(((4-(4-acryloylpiperazin-1-yl)-7-(3-hydroxynaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)oxy)methyl)piperidin-2-one

Synthesized according to the method of Example 8, using6-(hydroxymethyl)piperidin-2-one in place of(S)-1-(dimethylamino)propan-2-ol in Step B and separated by chiralchromatography. Peak 1 was assigned the (R) stereochemistry but thisstereochemistry was not confirmed. ES+APCI MS m/z 543.2 [M+H]⁺.

Example 63

1-(4-(7-(3-hydroxynaphthalen-1-yl)-2-(((R)-1-((R)-3-methoxypyrrolidin-1-yl)propan-2-yl)oxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Synthesized according to the method of Example 8, using(R)-1-((R)-3-methoxypyrrolidin-1-yl)propan-2-ol in place of(S)-1-(dimethylamino)propan-2-ol in Step B. ES+APCI MS m/z 573.3 [M+H]⁺.

Example 64

1-(4-(7-(3-hydroxynaphthalen-1-yl)-2-(((R)-1-((S)-3-methoxypyrrolidin-1-yl)propan-2-yl)oxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Synthesized according to the method of Example 8, using(R)-1-((S)-3-methoxypyrrolidin-1-yl)propan-2-ol in place of(S)-1-(dimethylamino)propan-2-ol in Step B. ES+APCI MS m/z 573.3 [M+H]⁺.

Example 65

1-(4-(7-(3-hydroxynaphthalen-1-yl)-2-(((R)-1-((S)-3-hydroxypyrrolidin-1-yl)propan-2-yl)oxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Synthesized according to the method of Example 8, using(R)-1-((S)-3-((tert-butyldimethylsilyl)oxy)pyrrolidin-1-yl)propan-2-olin place of (S)-1-(dimethylamino)propan-2-ol in Step B. ES+APCI MS m/z559.3 [M+H]⁺.

Example 66

(S)-1-(4-(7-(3-hydroxynaphthalen-1-yl)-2-((1-methylpiperidin-3-yl)oxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Synthesized according to the method of Example 8, using(S)-1-methylpiperidin-3-ol in place of (S)-1-(dimethylamino)propan-2-olin Step B. ES+APCI MS m/z 529.3 [M+H]⁺.

Example 67

(R)-1-(4-(7-(3-hydroxynaphthalen-1-yl)-2-((1-methylpiperidin-3-yl)oxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Synthesized according to the method of Example 8, using(R)-1-methylpiperidin-3-ol in place of (S)-1-(dimethylamino)propan-2-olin Step B. ES+APCI MS m/z 529.3 [M+H]⁺.

Example 68

(R)-1-(4-(2-((1-(dimethylamino)propan-2-yl)oxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Synthesized according to the method of Example 8, using1-iodonaphthalene in place of (3-(methoxymethoxy)naphthalen-1-yltrifluoromethanesulfonate in Step D. ES+APCI MS m/z 501.3 [M+H]⁺.

Example 69

1-(4-(7-(isoquinolin-4-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Synthesized according to the method of Example 1, using4-bromoisoquinoline in place of 1-bromo-3-(methoxymethoxy)naphthalene inStep C. ES+APCI MS m/z 401.2 [M+H]⁺.

Example 70

1-(4-(7-(3-hydroxynaphthalen-1-yl)-2-((1-(methylamino)propan-2-yl)oxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Synthesized according to the method of Example 8, using1-(methylamino)propan-2-ol in place of (S)-1-(dimethylamino)propan-2-olin Step B. ES+APCI MS m/z 503.3 [M+H]⁺.

Example 71

1-(4-(7-(2-hydroxy-1-phenylethyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Synthesized according to the method of Example 1, using2-((tert-butyldimethylsilyl)oxy)-1-phenylethyl methanesulfonate in placeof 1-bromo-3-(methoxymethoxy)naphthalene in Step C. ES+APCI MS m/z 394.2[M+H]⁺.

Example 72

1-(4-(7-(3-hydroxynaphthalen-1-yl)-2-((1-methylpiperidin-3-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Synthesized according to the method of Example 8, using(1-methylpiperidin-3-yl)methanol in place of(S)-1-(dimethylamino)propan-2-ol in Step B. ES+APCI MS m/z 543.3 [M+H]⁺.

Example 73

1-(4-(2-(2-(dimethylamino)propoxy)-7-(3-hydroxynaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Synthesized according to the method of Example 8, using2-(dimethylamino)propan-1-ol in place of(S)-1-(dimethylamino)propan-2-ol in Step B. ES+APCI MS m/z 517.2 [M+H]⁺.

Example 74

1-(4-(7-(3-hydroxynaphthalen-1-yl)-2-(3-morpholinopropoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Synthesized according to the method of Example 8, using3-morpholinopropan-1-ol in place of (S)-1-(dimethylamino)propan-2-ol inStep B. ES+APCI MS m/z 559.3 [M+H]⁺.

Example 75

(R)-1-(4-(7-(3-hydroxynaphthalen-1-yl)-2-((1-(piperidin-1-yl)propan-2-yl)oxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Synthesized according to the method of Example 8, using(R)-1-(piperidin-1-yl)propan-2-ol in place of(S)-1-(dimethylamino)propan-2-ol in Step B. ES+APCI MS m/z 557.3 [M+H]⁺.

Example 76

(R)-1-(4-(7-(3-chloro-5-hydroxy-2-isopropylphenyl)-2-((1-(dimethylamino)propan-2-yl)oxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Synthesized according to the method of Example 8, using1-bromo-3-chloro-2-isopropyl-5-(methoxymethoxy)benzene in place of(3-(methoxymethoxy)naphthalen-1-yl trifluoromethanesulfonate in Step D.ES+APCI MS m/z 545.3 [M+H]⁺.

Example 77

1-(4-(2-(2-((1S,4R)-2-azabicyclo[2.2.1]heptan-2-yl)ethoxy)-7-(3-hydroxynaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Synthesized according to the method of Example 8, using2-((1S,4R)-2-azabicyclo[2.2.1]heptan-2-yl)ethan-1-ol in place of(S)-1-(dimethylamino)propan-2-ol in Step B. ES+APCI MS m/z 555.2 [M+H]⁺.

Example 78

(R)-1-(4-(2-((1-(dimethylamino)propan-2-yl)oxy)-7-(5-hydroxy-2-(trifluoromethoxy)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Synthesized according to the method of Example 8, using2-bromo-4-(methoxymethoxy)-1-(trifluoromethoxy)benzene in place of(3-(methoxymethoxy)naphthalen-1-yl trifluoromethanesulfonate in Step D.ES+APCI MS m/z 551.2 [M+H]⁺.

Example 79

(R)-1-(4-(2-((1-(dimethylamino)propan-2-yl)oxy)-7-(5-hydroxy-2-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Synthesized according to the method of Example 8, using2-bromo-4-(methoxymethoxy)-1-(trifluoromethyl)benzene in place of(3-(methoxymethoxy)naphthalen-1-yl trifluoromethanesulfonate in Step D.ES+APCI MS m/z 535.2 [M+H]⁺.

Example 80

1-(4-(7-(3-hydroxynaphthalen-1-yl)-2-((4-methylpiperazin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Synthesized according to the method of Example 8, using(4-methylpiperazin-2-yl)methanol in place of(S)-1-(dimethylamino)propan-2-ol in Step B. ES+APCI MS m/z 544.3 [M+H]⁺.

Example 81

1-(2-((4-(4-acryloylpiperazin-1-yl)-7-(3-hydroxynaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)oxy)ethyl)piperidine-4-carbonitrile

Synthesized according to the method of Example 8, using1-(2-hydroxyethyl)piperidine-4-carbonitrile in place of(S)-1-(dimethylamino)propan-2-ol in Step B. ES+APCI MS m/z 568.2 [M+H]⁺.

Example 82

1-(4-(7-(3-hydroxynaphthalen-1-yl)-2-(3-(4-methylpiperazin-1-yl)propoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Synthesized according to the method of Example 8,3-(4-methylpiperazin-1-yl)propan-1-ol in place of(S)-1-(dimethylamino)propan-2-ol in Step B. ES+APCI MS m/z 572.4 [M+H]⁺.

Example 83

1-(4-(2-(2-((2-hydroxyethyl)(methyl)amino)ethoxy)-7-(3-hydroxynaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Synthesized according to the method of Example 8, using2-((2-((tert-butyldimethylsilyl)oxy)ethyl)(methyl)amino)ethan-1-ol inplace of (S)-1-(dimethylamino)propan-2-ol in Step B. ES+APCI MS m/z533.3 [M+H]⁺.

Example 84

(R)-1-(4-(2-((1-(dimethylamino)propan-2-yl)oxy)-7-(2-fluoro-6-hydroxy-3-methylphenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Synthesized according to the method of Example 8, using2-bromo-3-fluoro-1-(methoxymethoxy)-4-methylbenzene in place of(3-(methoxymethoxy)naphthalen-1-yl trifluoromethanesulfonate in Step D.ES+APCI MS m/z 499.3 [M+H]⁺.

Example 85

1-(4-(7-(3-hydroxynaphthalen-1-yl)-2-(2-(pyrrolidin-1-yl)ethoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Synthesized according to the method of Example 8, using2-(pyrrolidin-1-yl)ethan-1-ol in place of(S)-1-(dimethylamino)propan-2-ol in Step B. ES+APCI MS m/z 529.2 [M+H]⁺.

Example 86

(R)-1-(4-(2-((1-(dimethylamino)propan-2-yl)oxy)-7-(2-hydroxy-5-(trifluoromethoxy)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Synthesized according to the method of Example 8, using2-bromo-1-(methoxymethoxy)-4-(trifluoromethoxy)benzene in place of(3-(methoxymethoxy)naphthalen-1-yl trifluoromethanesulfonate in Step D.ES+APCI MS m/z 551.2 [M+H]⁺.

Example 87

(R)-1-(4-(2-((1-(dimethylamino)propan-2-yl)oxy)-7-(3-fluoro-2-hydroxy-6-methylphenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Synthesized according to the method of Example 8, using2-bromo-4-fluoro-3-(methoxymethoxy)-1-methylbenzene in place of(3-(methoxymethoxy)naphthalen-1-yl trifluoromethanesulfonate in Step D.ES+APCI MS m/z 499.2 [M+H]⁺.

Example 88

(S)-1-(4-(7-(3-hydroxynaphthalen-1-yl)-2-(2-(2-methylpiperidin-1-yl)ethoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Synthesized according to the method of Example 8, using(S)-2-(2-methylpiperidin-1-yl)ethan-1-ol in place of(S)-1-(dimethylamino)propan-2-ol in Step B. ES+APCI MS m/z 557.2 [M+H]⁺.

Example 89

1-(4-(7-(3-hydroxynaphthalen-1-yl)-2-((1-methylpyrrolidin-3-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Synthesized according to the method of Example 8, using(1-methylpyrrolidin-3-yl)methanol in place of(S)-1-(dimethylamino)propan-2-ol in Step B. ES+APCI MS m/z 529.3 [M+H]⁺.

Example 90

1-(4-(7-(5-hydroxy-2-(trifluoromethoxy)phenyl)-2-(3-morpholinopropoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Synthesized according to the method of Example 8, using3-morpholinopropan-1-ol in place of (S)-1-(dimethylamino)propan-2-ol inStep B, and using 2-bromo-4-(methoxymethoxy)-1-(trifluoromethoxy)benzenein place of (3-(methoxymethoxy)naphthalen-1-yl trifluoromethanesulfonatein Step D. ES+APCI MS m/z 593.2 [M+H]⁺.

Example 91

(R)-1-(4-(2-((1-(dimethylamino)propan-2-yl)oxy)-7-(3-hydroxy-5-(trifluoromethoxy)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Synthesized according to the method of Example 8, using3-bromo-1-(methoxymethoxy)-5-(trifluoromethoxy)benzene in place of(3-(methoxymethoxy)naphthalen-1-yl trifluoromethanesulfonate in Step D.ES+APCI MS m/z 551.2 [M+H]⁺.

Example 92

1-(4-(7-(3-hydroxynaphthalen-1-yl)-2-(2-(4-methylpiperidin-1-yl)ethoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Synthesized according to the method of Example 8, using2-(4-methylpiperidin-1-yl)ethan-1-ol in place of(S)-1-(dimethylamino)propan-2-ol in Step B. ES+APCI MS m/z 557.2 [M+H]⁺.

Example 93

1-(4-(7-(3-hydroxynaphthalen-1-yl)-2-((4-morpholinobutan-2-yl)oxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Synthesized according to the method of Example 8, using4-morpholinobutan-2-ol in place of (S)-1-(dimethylamino)propan-2-ol inStep B. ES+APCI MS m/z 573.3 [M+H]⁺.

Example 94

(R)-1-(4-(2-((1-(dimethylamino)propan-2-yl)oxy)-7-(5-hydroxy-2-methoxyphenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Synthesized according to the method of Example 8, using3-bromo-1-(methoxymethoxy)-4-methoxybenzene in place of(3-(methoxymethoxy)naphthalen-1-yl trifluoromethanesulfonate in Step D.ES+APCI MS m/z 497.2 [M+H]⁺.

Example 95

(R)-1-(4-(2-((1-(dimethylamino)propan-2-yl)oxy)-7-(2-hydroxy-6-methylphenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Synthesized according to the method of Example 8, using2-bromo-1-(methoxymethoxy)-3-methylbenzene in place of(3-(methoxymethoxy)naphthalen-1-yl trifluoromethanesulfonate in Step D.ES+APCI MS m/z 481.2 [M+H]⁺.

Example 96

1-(4-(7-(5-hydroxy-2-isopropoxyphenyl)-2-(3-morpholinopropoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Synthesized according to the method of Example 8, using3-morpholinopropan-1-ol in place of (S)-1-(dimethylamino)propan-2-ol inStep B, and using 2-bromo-4-(methoxymethoxy)-1-(isopropoxy)benzene inplace of (3-(methoxymethoxy)naphthalen-1-yl trifluoromethanesulfonate inStep D. ES+APCI MS m/z 567.2 [M+H]⁺.

Example 97

(R)-1-(4-(7-(3-hydroxynaphthalen-1-yl)-2-(2-(2-methylpiperidin-1-yl)ethoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Synthesized according to the method of Example 8, using(R)-2-(2-methylpiperidin-1-yl)ethan-1-ol in place of(S)-1-(dimethylamino)propan-2-ol in Step B. ES+APCI MS m/z 557.3

Example 98

(S)-1-(4-(7-(3-hydroxynaphthalen-1-yl)-2-(2-(3-methoxypiperidin-1-yl)ethoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Synthesized according to the method of Example 8, using(S)-2-(3-methoxypiperidin-1-yl)ethan-1-ol in place of(S)-1-(dimethylamino)propan-2-ol in Step B. ES+APCI MS m/z 557.3 [M+H]⁺.

Example 99

(R)-1-(4-(7-(3-hydroxynaphthalen-1-yl)-2-(2-(3-methoxypiperidin-1-yl)ethoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Synthesized according to the method of Example 8, using(R)-2-(3-methoxypiperidin-1-yl)ethan-1-ol in place of(S)-1-(dimethylamino)propan-2-ol in Step B. ES+APCI MS m/z 557.3 [M+H]⁺.

Example 100

1-(4-(2-((1-cyclopropylpiperidin-4-yl)oxy)-7-(3-hydroxynaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Synthesized according to the method of Example 8, using(1-cyclopropylpiperidin-4-ol in place of(S)-1-(dimethylamino)propan-2-ol in Step B. ES+APCI MS m/z 555.3 [M+H]⁺.

Example 101

1-(4-(2-(3-(1,4-oxazepan-4-yl)propoxy)-7-(3-hydroxynaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Synthesized according to the method of Example 8, using(3-(1,4-oxazepan-4-yl)propan-1-ol in place of(S)-1-(dimethylamino)propan-2-ol in Step B. ES+APCI MS m/z 573.3 [M+H]⁺.

Example 102

1-(4-(2-(3-(1,4-oxazepan-4-yl)propoxy)-7-(3-hydroxynaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Synthesized according to the method of Example 8, using2-(diethylamino)ethan-1-ol in place of (S)-1-(dimethylamino)propan-2-olin Step B. ES+APCI MS m/z 531.3 [M+H]⁺.

Example 103

1-(4-(7-(3-hydroxynaphthalen-1-yl)-2-((1-(2-methoxyethyl)pyrrolidin-3-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Synthesized according to the method of Example 8,(1-(2-methoxyethyl)pyrrolidin-3-yl)methanol in place of(S)-1-(dimethylamino)propan-2-ol in Step B. ES+APCI MS m/z 573.3 [M+H]⁺.

Example 104

1-(4-(2-(3-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)propoxy)-7-(3-hydroxynaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Synthesized according to the method of Example 8, using3-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)propan-1-ol in place of(S)-1-(dimethylamino)propan-2-ol in Step B. ES+APCI MS m/z 571.3 [M+H]⁺.

Example 105

1-(4-(7-(5-hydroxy-2-methylphenyl)-2-(3-morpholinopropoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Synthesized according to the method of Example 8, using3-morpholinopropan-1-ol in place of (S)-1-(dimethylamino)propan-2-ol inStep B, and using 2-bromo-4-(methoxymethoxy)-1-methylbenzene in place of(3-(methoxymethoxy)naphthalen-1-yl trifluoromethanesulfonate in Step D.ES+APCI MS m/z 523.3 [M+H]⁺.

Example 106

1-(4-(7-(4-hydroxy-2-(trifluoromethoxy)phenyl)-2-(3-morpholinopropoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Synthesized according to the method of Example 8, using3-morpholinopropan-1-ol in place of (S)-1-(dimethylamino)propan-2-ol inStep B, and using 2-bromo-5-(methoxymethoxy)-1-(trifluoromethoxy)benzenein place of (3-(methoxymethoxy)naphthalen-1-yl trifluoromethanesulfonatein Step D. ES+APCI MS m/z 593.2 [M+H]⁺.

Example 107

1-(4-(7-(3-hydroxynaphthalen-1-yl)-2-(2-((2-methoxyethyl)(methyl)amino)ethoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Synthesized according to the method of Example 8, using2-((2-methoxyethyl)(methyl)amino)ethan-1-ol in place of(S)-1-(dimethylamino)propan-2-ol in Step B. ES+APCI MS m/z 547.3 [M+H]⁺.

Example 108

1-(4-(7-(3-hydroxynaphthalen-1-yl)-2-(2-(4-methoxypiperidin-1-yl)ethoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Synthesized according to the method of Example 8, using2-(4-methoxypiperidin-1-yl)ethan-1-ol in place of(S)-1-(dimethylamino)propan-2-ol in Step B. ES+APCI MS m/z 573.3 [M+H]⁺.

Example 109

1-(4-(2-(2-(4,4-difluoropiperidin-1-yl)ethoxy)-7-(3-hydroxynaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Synthesized according to the method of Example 8, using2-(4,4-difluoropiperidin-1-yl)ethan-1-ol in place of(S)-1-(dimethylamino)propan-2-ol in Step B. ES+APCI MS m/z 579.2 [M+H]⁺.

Example 110

(R)-1-(4-(7-(3-hydroxynaphthalen-1-yl)-2-((1-methylpyrrolidin-3-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Synthesized according to the method of Example 8, using(R)-(1-methylpyrrolidin-3-yl)methanol in place of(S)-1-(dimethylamino)propan-2-ol in Step B. ES+APCI MS m/z 529.3 [M+H]⁺.

Example 111

(S)-1-(4-(2-(2-(3-fluoropiperidin-1-yl)ethoxy)-7-(3-hydroxynaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Synthesized according to the method of Example 8, using(S)-2-(3-fluoropiperidin-1-yl)ethan-1-ol in place of(S)-1-(dimethylamino)propan-2-ol in Step B. ES+APCI MS m/z 561.3 [M+H]⁺.

Example 112

1-(4-(7-(3-(difluoromethyl)naphthalen-1-yl)-2-(3-morpholinopropoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Synthesized according to the method of Example 8, using3-morpholinopropan-1-ol in place of (S)-1-(dimethylamino)propan-2-ol inStep B, and using 1-bromo-3-(difluoromethyl)naphthalene (0.129 g, 0.503mmol) in place of (3-(methoxymethoxy)naphthalen-1-yltrifluoromethanesulfonate in Step D. ES+APCI MS m/z 593.2 [M+H]⁺.

Example 113

4-(4-acryloylpiperazin-1-yl)-7-(3-hydroxynaphthalen-1-yl)-7,8-dihydropyrido[3,4-d]pyrimidin-6(5H)-oneStep A: tert-butyl4-(6-fluoropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate

To a solution of 4-chloro-6-fluoropyrido[3,4-d]pyrimidine (1.07 g, 5.83mmol) in DCM (20 mL) was added N-ethyl-N-isopropylpropan-2-amine (2.09mL, 11.7 mmol) followed by tert-butyl piperazine-1-carboxylate (1.19 g,6.41 mmol) and the reaction stirred at room temperature for 2 hours. Thereaction mixture was washed with brine, dried over MgSO4 andconcentrated in vacuo to provide tert-butyl4-(6-fluoropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate, whichwas used directly in the next step (1.8 g, 92.6%) ES+APCI MS m/z 334.1[M+H]⁺.

Step B: tert-butyl4-(6-(benzyloxy)pyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate

To a solution of phenylmethanol (0.65 g, 6.0 mmol) in DMA (10 mL) wasadded sodium hydride (0.24 g, 6.0 mmol) in portions while degassing withnitrogen and the reaction mixture was stirred for 30 minutes at roomtemperature. To the reaction was added tert-butyl4-(6-fluoropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate (1.0 g,3.0 mmol) as a solid and the reaction mixture was stirred at roomtemperature for 3 hours. The reaction was poured into water (300 mL) andthe aqueous layer extracted with ethyl acetate. The organic layer waswashed with brine, dried over MgSO4 and concentrated in vacuo. The crudematerial was chromatographed using a gradient of 0 to 100% ethylacetate/DCM as the eluent to give tert-butyl4-(6-(benzyloxy)pyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(0.4 g, 0.95 mmol, 32% yield). ES+APCI MS m/z 422.2 [M+H]⁺.

Step C: tert-butyl4-(6-oxo-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate

To a solution of tert-butyl4-(6-(benzyloxy)pyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(0.40 g, 0.95 mmol) in 95% ethanol (30 mL) purged with nitrogen wasadded Pd/C (0.10 g, 0.95 mmol). The reaction was evacuated with vacuumand backfilled with hydrogen three times. After the third backfill thereaction mixture was stirred at room temperature for 4 hours. Thereaction was again degassed with nitrogen, the slurry filtered throughCelite® and the filtrate was concentrated in vacuo to give tert-butyl4-(6-oxo-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(0.4 g, 126%). ES+APCI MS m/z 334.4 [M+H]⁺.

Step D: tert-butyl4-(7-(3-(methoxymethoxy)naphthalen-1-yl)-6-oxo-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate

To a solution of tert-butyl4-(6-oxo-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(0.28 g, 0.84 mmol) in dioxanes (4 mL) in a sealed tube was addedpotassium phosphate (0.36 g, 1.7 mmol), N1,N2-dimethylethane-1,2-diamine(0.074 g, 0.84 mmol) and 1-iodo-3-(methoxymethoxy)naphthalene (0.53 g,1.7 mmol). The reaction sparged with argon for 20 minutes, followed byaddition of copper(I) iodide (0.16 g, 0.84 mmol). The reaction vesselsealed and heated to 100° C. overnight. The reaction was diluted withwater and the aqueous layer extracted with ethyl acetate (2×150 mL). Theorganics were washed with brine, dried over MgSO4 and concentrated invacuo. The material was chromatographed using a gradient of 0 to 100%ethyl acetate/DCM as the eluent to give tert-butyl4-(7-(3-(methoxymethoxy)naphthalen-1-yl)-6-oxo-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(0.30 g, 0.58 mmol, 69% yield) ES+APCI MS m/z 520.2 [M+H]⁺.

Step E:7-(3-hydroxnaphthalen-1-yl)-4-(piperazin-1-yl)-7,8-dihydropyrido[3,4-d]pyrimidin-6(5H)-one

To a solution of tert-butyl4-(7-(3-(methoxymethoxy)naphthalen-1-yl)-6-oxo-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(0.30 g, 0.58 mmol) in methanol (10 mL) was added aqueous hydrogenchloride (0.38 mL, 2.3 mmol) and the reaction stirred over night at 50°C. The reaction was concentrated in vacuo to give7-(3-hydroxynaphthalen-1-yl)-4-(piperazin-1-yl)-7,8-dihydropyrido[3,4-d]pyrimidin-6(5H)-oneas the bis HCl salt (0.26 g, 100%). ES+APCI MS m/z 376.1 [M+H]⁺.

Step F:4-(4-acryloylpiperazin-1-yl)-7-(3-hydroxynaphthalen-1-yl)-7,8-dihydropyrido[3,4-d]pyrimidin-6(5H)-one

To a slurry of7-(3-hydroxynaphthalen-1-yl)-4-(piperazin-1-yl)-7,8-dihydropyrido[3,4-d]pyrimidin-6(5H)-onedihydrochloride (0.26 g, 0.58 mmol) in a 1:1 solution ofDCM/acetonitrile (10 mL) was added N-ethyl-N-isopropylpropan-2-amine(0.45 g, 3.5 mmol) and acryloyl chloride (0.052 g, 0.58 mmol) and thereaction stirred at room temperature for 1 hour. The reaction wasconcentrated in vacuo and the material purified by reverse preparativeHPLC (using a gradient of 5 to 95% ACN/water) to give4-(4-acryloylpiperazin-1-yl)-7-(3-hydroxynaphthalen-1-yl)-7,8-dihydropyrido[3,4-d]pyrimidin-6(5H)-one(0.038 g, 0.088 mmol, 15% yield). ES+APCI MS m/z 430.2 [M+H]⁺.

Example 114

4-(6-acryloyl-2,6-diazaspiro[3.3]heptan-2-yl)-7-(3-hydroxynaphthalen-1-yl)-7,8-dihydropyrido[3,4-d]pyrimidin-6(5H)-one

Synthesized according to the method of Example 8, using tert-butyl2,6-diazaspiro[3.3]heptane-2-carboxylate hydrochloride (305 mg, 1.54mmol) in place of tert-butyl piperazine-1-carboxylate (1.19 g, 6.41mmol) in Step B. ES+APCI MS m/z 442.2 [M+H]⁺

Example 115

1-((S)-4-(2-(((R)-1-(dimethylamino)propan-2-yl)oxy)-7-(3-hydroxynaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-3-methylpiperazin-1-yl)prop-2-en-1-one

Synthesized according to the method of Example 8, using benzyl(S)-3-methylpiperazine-1-carboxylate (1.155 g, 4.931 mmol) in place ofBenzyl 1-piperazinecarboxylate in step A. ES+APCI MS m/z 531.3 [M+H]⁺.

Example 116

(S)-1-(4-(2-(2-(dimethylamino)ethoxy)-7-(3-hydroxynaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-3-methylpiperazin-1-yl)prop-2-en-1-one

Synthesized according to the method of Example 8, using benzyl(S)-3-methylpiperazine-1-carboxylate (1.155 g, 4.931 mmol) in place ofBenzyl 1-piperazinecarboxylate in step A. Also, using2-(dimethylamino)ethan-1-ol in place of (S)-1-(dimethylamino)propan-2-olin Step B. ES+APCI MS m/z 517.3 [M+H]⁺.

Example 117

1-(4-(7-(3-hydroxynaphthalen-1-yl)-2-(2-morpholinoethoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Synthesized according to the method of Example 8, using2-morpholinoethan-1-ol in place of (S)-1-(dimethylamino)propan-2-ol inStep B. ES+APCI MS m/z 545.2 [M+H]⁺.

Example 118

1-(4-(7-(3-hydroxynaphthalen-1-yl)-2-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Synthesized according to the method of Example 8, using morpholine inplace of (S)-1-(dimethylamino)propan-2-ol in Step B. ES+APCI MS m/z501.3 [M+H]⁺.

Example 119

1-(4-(7-(3-hydroxynaphthalen-1-yl)-2-(pyrrolidin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Synthesized according to the method of Example 8, using pyrrolidine inplace of (S)-1-(dimethylamino)propan-2-ol in Step B. ES+APCI MS m/z485.2 [M+H]⁺.

Example 120

(R)-1-(4-(7-(3-hydroxynaphthalen-1-yl)-2-((1-(pyrrolidin-1-yl)propan-2-yl)oxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Synthesized according to the method of Example 8, using(R)-1-(pyrrolidin-1-yl)propan-2-ol in place of(S)-1-(dimethylamino)propan-2-ol in Step B. ES+APCI MS m/z 543.4 [M+H]⁺.

Example 121

4-(4-acryloylpiperazin-1-yl)-7-(3-hydroxynaphthalen-1-yl)-2-(3-morpholinopropoxy)-6,7-dihydropyrido[3,4-d]pyrimidin-8(5H)-oneStep A: Tert-butyl2,4-dichloro-8-oxo-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate

To a round bottom flask was added tert-Butyl2,4-dichloro-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate (1.0g, 3.29 mmol) and EtOAc (16.4 mL). A solution of sodium periodate (2.11g, 9.86 mmol) in water (16.4 mL) was added. Ruthenium (III) chloride(0.102 g, 0.493 mmol) was added and the mixture was stirred looselycapped and vigorously stirred for 6 h at ambient temperature. Themixture was partitioned between water and EtOAc and the layers wereseparated. The aqueous layer was extracted further with EtOAc (2×20 mL)and the combined extracts were washed with brine and dried over Na₂SO₄,filtered and concentrated. The crude product was purified via columnchromatography (10-30% EtOAc/hexanes, loading with CH2C2) to afford0.864 g (82%) of the product as an off-white solid.

Step B: Tert-butyl4-(4-((benzyloxy)carbonyl)piperazin-1-yl)-2-chloro-8-oxo-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate

To a solution of tert-butyl2,4-dichloro-8-oxo-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate(0.400 g, 1.26 mmol) in CH2C12 (5.0 mL) was addedN,N-Diisopropylethylamine (0.325 g, 2.51 mmol) followed by benzyl1-piperazinecarboxylate (0.255 mL, 1.32 mmol) and the reaction stirredat ambient temperature for 1.5 h. The reaction mixture was diluted withCH2C2 (10 mL) and washed with a 0.5M KHSO₄ solution (5 mL), followed bya saturated aqueous NaHCO₃ solution and brine. The organic layer wasdried over Na₂SO₄, filtered and concentrated. The crude product wassonicated in 10 mL MTBE and the resulting solid was isolated by vacuumfiltration. The solid was dried in vacuo to provide 0.507 g (80%) of thedesired product as an off-white solid which was used directly in thenext step. ES+APCI MS m/z 502.1[M+H]⁺.

Step C: Benzyl4-(2-chloro-8-oxo-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate

A solution of tert-butyl4-(4-((benzyloxy)carbonyl)piperazin-1-yl)-2-chloro-8-oxo-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate(0.255 g, 0.5080 mmol) in CH₂Cl₂ (1.0 mL) was cooled to 0° C.Trifluoroacetic acid (0.3890 mL, 5.080 mmol) was added and the mixturewas warmed to ambient temperature. After 1 hour the mixture was dilutedwith CH2C2 and added to a mixture brine (10 mL) and 3.0 M aqueous NaOH(1.7 mL, 5.080 mmol). The layers were combined and adjusted to pH 8 withsaturated aqueous NaHCO₃ solution. The layers were separated and theaqueous phase was extracted with 2×10 mL of CH2C12. The combined organiclayers were dried over Na₂SO₄, filtered and concentrated under vacuum.The title compound (0.223 g, quant.) was obtained as a yellow/orangefoam. ES+APCI MS m/z 402.1[M+H]⁺.

Step D: Benzyl4-(2-(3-morpholinopropoxy)-8-oxo-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate

To a vial was added N-Hydroxypropanylmorpholine (0.687 g, 4.73 mmol) andbenzyl4-(2-chloro-8-oxo-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(0.190 g, 0.473 mmol) followed by dioxane (1.6 mL). Cesium carbonate(0.462 g, 1.42 mmol) was added and the mixture was stirred at 65° C. for15 hours. The mixture was diluted with CHCl₃ and filtered, and the solidwas washed with additional CHCl₃. The filtrate was concentrated in vacuoand was purified by column chromatography (2-10% MeOH/DCM with 1% NH₄OH)to afford 0.061 g (25%) of the desired product as a thick, colorlessoil. ES+APCI MS m/z 511.2[M+H]⁺.

Step E: Benzyl4-(7-(3-(methoxymethoxy)naphthalen-1-yl)-2-(3-morpholinopropoxy)-8-oxo-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate

To a vial was added benzyl4-(2-(3-morpholinopropoxy)-8-oxo-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(0.060 g, 0.12 mmol), N,N′-Dimethylethylenediamine (0.010 g, 0.12 mmol)and 1-iodo-3-(methoxymethoxy)naphthalene (0.074 g, 0.24 mmol) followedby dioxane (0.78 mL) and Potassium phosphate tribasic (0.050 g, 0.24mmol). The reaction was purged with bubbling Ar for 10 min, then Copper(I) Iodide (0.022 g, 0.12 mmol) was added and the vial was sealed. Themixture was heated to 110° C. and stirred for 16 hours. The mixture wascooled to ambient temperature, diluted with water and extracted withEtOAc (3×10 mL). The combined organic extracts were dried over Na₂SO₄,filtered and concentrated. The mixture was purified via columnchromatography (2-8% MeOH/DCM) to afford 0.062 g (76%) of the product asa tan foam. ES+APCI MS m/z 697.3[M+H]⁺.

Step F:7-(3-(methoxymethoxy)naphthalen-1-yl)-2-(3-morpholinopropoxy)-4-(piperazin-1-yl)-6,7-dihydropyrido[3,4-d]pyrimidin-8(5H)-one

To a solution of benzyl4-(7-(3-(methoxymethoxy)naphthalen-1-yl)-2-(3-morpholinopropoxy)-8-oxo-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(0.062 g, 0.089 mmol) in EtOH (0.44 mL) and THE (0.44 mL) was addedPalladium on Carbon (0.038 g, 0.018 mmol) (Degussa Type, 10 wt %, 50%H₂O) and then an atmosphere of hydrogen was introduced via vacuumfollowed by balloon pressure. The mixture was stirred at ambienttemperature for 1.5 h, then warmed to 45° C. and stirred for 1 hour. Themixture was diluted with EtOAc and filtered through a nylon filter. Thefiltrate was concentrated in vacuo providing a light tan foam (0.052 g)that was dried overnight and resubmitted to the same reaction conditionsabove. After stirring at ambient temperature for 5 h additional Pd/C(0.050 g) was added and the reaction was stirred at ambient temperaturefor another 2 h. The mixture was diluted with EtOAc and filtered througha nylon filter. The solid was washed with EtOAc and MeOH and thefiltrate was concentrated in vacuo providing 0.029 g (58%) of thedesired product as a light tan foam. ES+APCI MS m/z 563.3[M+H]⁺.

Step G:4-(4-acryloylpiperazin-1-yl)-7-(3-(methoxymethoxy)naphthalen-1-yl)-2-(3-morpholinopropoxy)-6,7-dihydropyrido[3,4-d]pyrimidin-8(5H)-one

To a solution of7-(3-(methoxymethoxy)naphthalen-1-yl)-2-(3-morpholinopropoxy)-4-(piperazin-1-yl)-6,7-dihydropyrido[3,4-d]pyrimidin-8(5H)-one(0.028 g, 0.050 mmol) in CH2C12 (0.50 mL) at −78° C. was addedTriethylamine (0.014 mL, 0.100 mmol). Acryloyl chloride (0.55 mL, 0.055mmol, freshly prepared 0.1M CH2C2) was added and the reaction was thenstirred for 0.5 h. The mixture was diluted with CHCl₃ and a saturatedaqueous NH₄Cl solution was added. The layers were separated and theaqueous layer was extracted with CHCl₃ (2×10 mL). The combined extractswere dried over Na₂SO₄, filtered and concentrated. The crude product waspurified via column chromatography (4-6% MeOH/DCM) to afford 0.018 g(59%) to provide the title compound as a solid off-white foam. ES+APCIMS m/z 617.3[M+H]⁺.

Step H:4-(4-acryloylpiperazin-1-yl)-7-(3-hydroxynaphthalen-1-yl)-2-(3-morpholinopropoxy)-6,7-dihydropyrido[3,4-d]pyrimidin-8(5H)-one

To a solution of4-(4-acryloylpiperazin-1-yl)-7-(3-(methoxymethoxy)naphthalen-1-yl)-2-(3-morpholinopropoxy)-6,7-dihydropyrido[3,4-d]pyrimidin-8(5H)-one(0.018 g, 0.0292 mmol) in 1/1 MeOH/THF (0.6 mL) was added HCl (0.0486mL, 0.292 mmol, 6 N Aqueous). The mixture was stirred at 35° C. for 7hours. The mixture was diluted with brine and adjusted to pH 8 with asaturated aqueous NaHCO₃ solution. The mixture was extracted with 10%IPA/CHCl₃ (2×10 mL) and CHCl₃ (10 mL). The combined organic layers weredried over Na₂SO₄, filtered and concentrated. The crude material waspurified via column chromatography (6-10% MeOH/DCM) to afford 0.012 g(71%) of the product as an off-white solid. ES+APCI MS m/z 573.3[M+H]⁺.

Example 122

(R,E)-4-(dimethylamino)-1-(4-(2-((1-(dimethylamino)propan-2-yl)oxy)-7-(3-hydroxynaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)but-2-en-1-onebis-trifluoroacetate

Steps A-E

(R)-2-((7-(3-(methoxymethoxy)naphthalen-1-yl)-4-(piperazin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)oxy)-N,N-dimethylpropan-1-aminewas synthesized according to the method of Example 8, Step A throughStep E, using (R)-1-(dimethylamino)propan-2-ol in place of(S)-1-(dimethylamino)propan-2-ol in Step B.

Step F:(R)-4-(2-((1-(Dimethylaminopropan-2-yl)oxy)-4-(piperazin-1-yl)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)naphthalen-2-oldihydrochloride

To a solution of(R)-2-((7-(3-(methoxymethoxy)naphthalen-1-yl)-4-(piperazin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)oxy)-N,N-dimethylpropan-1-amine(75 mg, 0.15 mmol) in DCM (2.9 mL) was added 6N HCl in iPrOH (247 μl,1.5 mmol) and the mixture was stirred at ambient temperature for 1 h.The reaction mixture was concentrated to dryness to provide(R)-4-(2-((1-(Dimethylamino)propan-2-yl)oxy)-4-(piperazin-1-yl)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)naphthalen-2-oldihydrochloride which was used directly in the next stop. ES+APCI MS m/z463.2 [M+H]⁺.

Step G:(R,E)-4-(Dimethylamino)-1-(4-(2-((1-(dimethylamino)propan-2-yl)oxy)-7-(3-hydroxynaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)but-2-en-1-onebis-trifluoroacetate

A solution of(R)-4-(2-((1-(Dimethylamino)propan-2-yl)oxy)-4-(piperazin-1-yl)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)naphthalen-2-oldihydrochloride (7 mg, 0.01 mmol), HATU (6.2 mg, 0.02 mmol),(2E)-4-(dimethylamino)but-2-enoic acid (2.1 mg, 0.02 mmol), DIEA (6.9μl, 0.04 mmol) in DCM (131 μl) was stirred at ambient temperature for 1h. The residue was filtered and the filtrate was loaded directly onto aGilson C18 prep HPLC eluting with 5-95% acetonitrile/water with 0.1% TFAadditive. The fractions containing the desired product were concentratedto provide(R,E)-4-(Dimethylamino)-1-(4-(2-((1-(dimethylamino)propan-2-yl)oxy)-7-(3-hydroxynaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)but-2-en-1-onebis-trifluoroacetate. ES+APCI MS m/z 574.2 [M+H]⁺.

Example 123

1-(4-(2-(2-hydroxy-3-morpholinopropoxy)-7-(3-hydroxynaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Synthesized according to the method of Example 8, using3-morpholinopropane-1,2-diol in place of(S)-1-(dimethylamino)propan-2-ol in Step B. ES+APCI MS m/z 575.2 [M+H]⁺.

Example 124

(R)-1-(4-(2-((1-(dimethylamino)propan-2-yl)oxy)-7-(4-fluoro-3-hydroxynaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Step A: Benzyl(R)-4-(2-((1-(dimethylamino)propan-2-yl)oxy)-7-(3-(methoxymethoxy)naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(221 mg, 0.345 mmol) was placed in ACN (2 mL) and the mixture was cooledto 0° C. SelectFluor (183 mg, 0.517 mmol) was added and the reaction wasstirred at room temperature for 30 minutes. Water was added and themixture was extracted with DCM. The organic layers were combined andconcentrated. The resulting residue was purified by reverse phasechromatography (5-95% ACN:water with 0.1% TFA) to provide benzyl(R)-4-(2-((1-(dimethylamino)propan-2-yl)oxy)-7-(4-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylatetrifluoroacetate (48 mg, 0.0729 mmol, 21.1% yield).

Step B:(R)-1-(4-(2-((1-(dimethylamino)propan-2-yl)oxy)-7-(4-fluoro-3-hydroxynaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-onewas prepared following Example 33, Steps D-F substituting(R)-4-(2-((1-(dimethylamino)propan-2-yl)oxy)-7-(4-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylatetrifluoroacetate for benzyl4-(7-(3-(methoxymethoxy)naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate.ES+APCI MS m/z 535.2 [M+H]⁺.

Example 125

(R)-1-(4-(7-(4-chloro-3-hydroxynaphthalen-1-yl)-2-((1-(dimethylamino)propan-2-yl)oxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Step A: Benzyl(R)-4-(2-((1-(dimethylamino)propan-2-yl)oxy)-7-(3-(methoxymethoxy)naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(83 mg, 0.130 mmol) and NCS (21.6 mg, 0.162 mmol) were placed in ACN (2mL) and stirred at room temperature for 3 hours. Water was added and themixture was extracted with DCM (3×15 mL). The organic layers werecombined and concentrated. The resulting residue was purified by reversephase chromatography (5-95% ACN:water with 0.1% TFA) to provide benzyl(R)-4-(7-(4-chloro-3-(methoxymethoxy)naphthalen-1-yl)-2-((1-(dimethylamino)propan-2-yl)oxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylatetrifluoroacetate (17 mg, 0.0252 mmol, 19.4% yield).

Step B:(R)-1-(4-(7-(4-chloro-3-hydroxynaphthalen-1-yl)-2-((1-(dimethylamino)propan-2-yl)oxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-onewas prepared following Example 33, Steps D-F substituting(R)-4-(7-(4-chloro-3-(methoxymethoxy)naphthalen-1-yl)-2-((1-(dimethylamino)propan-2-yl)oxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylatetrifluoroacetate for benzyl4-(7-(3-(methoxymethoxy)naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylateand using THE as the solvent in Step D. ES+APCI MS m/z 551.2 [M+H]⁺.

Example 126

1-(4-(7-(3-hydroxynaphthalen-1-yl)-2-(2-(pyridin-2-yl)ethoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-oneTrifluoroacetate Step A: benzyl4-(7-(3-(methoxymethoxy)naphthalen-1-yl)-2-(2-(pyridin-2-yl)ethoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate

To a slurry of benzyl4-(2-chloro-7-(3-(methoxymethoxy)naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(0.20 g, 0.35 mmol) in dioxane in a microwave was addedN-ethyl-N-isopropylpropan-2-amine (0.45 g, 3.5 mmol), Cs₂CO₃ (0.34 g,1.0 mmol) and 2-(pyridin-2-yl)ethan-1-ol (0.43 g, 3.5 mmol) and thereaction heated to 15° C. for 1 hr in the microwave. The reaction wasdiluted with EtOAc and washed with water, brine, dried over MgSO4 andconcentrated in vacuo. The material was chromatographed using a gradientof 0 to 100% EtOAc/DCM as the eluent to give benzyl4-(7-(3-(methoxymethoxy)naphthalen-1-yl)-2-(2-(pyridin-2-yl)ethoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(0.16 g, 0.24 mmol, 70% yield).

Step B:4-(4-(piperazin-1-yl)-2-(2-(pyridin-2-yl)ethoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)naphthalen-2-ol

To the solid benzyl4-(7-(3-(methoxymethoxy)naphthalen-1-yl)-2-(2-(pyridin-2-yl)ethoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(0.12 g, 0.18 mmol) was added MeOH (20 mL). The solution was degassedwith nitrogen 5 minutes, followed by addition of Pd/C (0.058 g, 0.54mmol). The reaction vessel was evacuated by vacuum and backfilled withH₂. This procedure was performed three times, and after the thirdbackfill the slurry was left to sir under an atmosphere of hydrogen for1 hr. The reaction was again degassed with nitrogen for 5 minutes. Theslurry was next filtered through Celite® and the Celite® was washed withMeOH (100 mL). The combined organic extracts were concentrated andtreated with 10 mL of 1:1 TFA/DCM for 2 hrs. The reaction was againconcentrated in vacuo to give4-(4-(piperazin-1-yl)-2-(2-(pyridin-2-yl)ethoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)naphthalen-2-ol(0.096 g, 0.20 mmol, 110% yield).

Step C:1-(4-(7-(3-hydroxynaphthalen-1-yl)-2-(2-(pyridin-2-yl)ethoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

To a solution of4-(4-(piperazin-1-yl)-2-(2-(pyridin-2-yl)ethoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)naphthalen-2-ol(0.096 g, 0.20 mmol) in DCM was added Hunig's Base (0.17 mL, 0.99 mmol)and acryloyl chloride (0.018 g, 0.20 mmol) and the reaction stirred for30 minutes at room temperature. The reaction was concentrated in vacuoand the crude material was purified by reverse preparative HPLC to give1-(4-(7-(3-hydroxynaphthalen-1-yl)-2-(2-(pyridin-2-yl)ethoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-onetrifluoroacetate (0.0057 g, 0.011 mmol, 5.3% yield). ES+APCI MS m/z537.2 [M+H]⁺.

Example 127(S)-7-(3-(methoxymethoxy)naphthalen-1-yl)-2-((1-methylpyrrolidin-2-yl)methoxy)-4-(piperazin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine

Step A: tert-butyl4-(4-((benzyloxy)carbonyl)piperazin-1-yl)-2-chloro-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate

To a solution oftert-butyl2,4-dichloro-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate(8 g, 26.30 mmol) in DMA (263.0 ml, 26.30 mmol) was added benzylpiperazine-1-carboxylate (5.793 g, 26.30 mmol) andN-ethyl-N-isopropylpropan-2-amine (4.721 ml, 26.30 mmol) and thereaction stirred at room temperature for 2 hours. TLC (20% EtOAc/DCM),UV visualization, showed reaction completion. The reaction was nextpoured into water and extracted into DCM. The organics were next washedwith water (2×), brine, dried over MgSO4 and concentrated in vacuo. Theconcentrate was loaded onto a 220 g RegiSep column and chromatographedon the CombiFlash (0%-10%, EtOAc:DCM). All fractions containing desiredproduct were combined and concentrated to give tert-butyl4-(4-((benzyloxy)carbonyl)piperazin-1-yl)-2-chloro-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate(9.768 g, 20.02 mmol, 76.11% yield) as a white foam. ES+APCI MS m/z488.2 [M+H]⁺.

Step B: benzyl4-(2-chloro-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate

tert-butyl4-(4-((benzyloxy)carbonyl)piperazin-1-yl)-2-chloro-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate(9.768 g, 20.02 mmol) was dissolved in dichloromethane (200.2 ml, 20.02mmol) and treated with 2,2,2-trifluoroacetic acid (15.33 ml, 200.2mmol). The reaction mixture stirred at room temp for 4 hours. Aftercompletion the reaction was next concentrated in vacuo and taken up inEtOAc and the organics washed with 1M NaOH (2×), brine, dried over MgSO4and concentrated in vacuo. benzyl4-(2-chloro-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(7.406 g, 19.09 mmol, 95.39% yield) was used crude in the next reaction.ES+APCI MS m/z 388.2 [M+H]⁺.

Step C: benzyl4-(2-chloro-7-(3-(methoxymethoxy)naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate

To the benzyl4-(2-chloro-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate,BINAP (0.275 g, 0.442 mmol) and Pd₂(dba)₃ (0.203 g, 0.221 mmol) underargon was added toluene (221 ml, 11.1 mmol) and the reaction bubbledwith Ar for 10 minutes followed by heating to 100° C. for 10 minutes.The reaction was next cooled to room temperature and benzyl4-(2-chloro-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(4.29 g, 11.1 mmol) and Sodium Tert-Butoxide (2.13 g, 22.1 mmol) wereadded to the dark solution as solids. Finally,3-(methoxymethoxy)naphthalen-1-yl trifluoromethanesulfonate (7.44 g,22.1 mmol) was added (as the oil) and the reaction heated to 100° C. for1 hour. The reaction was cooled to room temperature and concentrated invacuo. The concentrate was dissolved with EtOAc and washed with waterand brine. The combined organics were dried over Na₂SO₄ and concentratedin vacuo. The residue was then loaded on the CombiFlash andchromatographed using 0%->50% Hexane:EtOAc as eluent. Fractionscontaining clean product were combined and concentrated in vacuo toafford benzyl4-(2-chloro-7-(3-(methoxymethoxy)naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(2.6 g, 4.53 mmol, 40.9% yield). ES+APCI MS m/z 574.2 [M+H]⁺.

Step D: benzyl(S)-4-(7-(3-(methoxymethoxy)naphthalen-1-yl)-2-((1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate

In a microwave tube benzyl4-(2-chloro-7-(3-(methoxymethoxy)naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(300 mg, 0.523 mmol) was dissolved in Dioxane (6532 μl, 0.523 mmol) andtreated with cesium carbonate (511 mg, 1.57 mmol), Hunig's base (913 μl,5.23 mmol) and N-Methyl-L-prolinol (421 mg, 3.66 mmol). The tube wasthen capped and microwaved at 170° C. for 3 hours. The reaction wasfiltered through GF/F paper. The filtrate was concentrated in vacuo andthe residue loaded onto a 12 g RegiSep gold column and chromatographedon the CombiFlash (0%-15%, DCM:MeOH). All fractions containing cleanproduct were combined and concentrated in vacuo to give benzyl(S)-4-(7-(3-(methoxymethoxy)naphthalen-1-yl)-2-((1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(220 mg, 0.337 mmol, 64.5% yield). ES+APCI MS m/z 653.3 [M+H]⁺.

Step E:(S)-7-(3-(methoxymethoxy)naphthalen-1-yl)-2-((1-methylpyrrolidin-2-yl)methoxy)-4-(piperazin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine

A solution ofbenzyl(S)-4-(7-(3-(methoxymethoxy)naphthalen-1-yl)-2-((1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(220 mg, 0.337 mmol) in EtOH (3370 μl, 0.337 mmol) and THF (3370 μl,0.337 mmol) was purged with N₂ for 5 minutes. To this solution was addedPalladium on carbon (179 mg, 0.0843 mmol) (Degussa Type, 10 wt %, 50%H₂O), and was immediately capped and purged with N₂ for an additional 5min. The solution then stirred under H₂ introduced via vacuum followedby balloon pressure. The mixture was then stirred at ambient temperatureover night. LC/MS showed reaction completion. The mixture was dilutedwith MeOH and filtered through packed celite. The filtrate was thenconcentrated in vacuo and(S)-7-(3-(methoxymethoxy)naphthalen-1-yl)-2-((1-methylpyrrolidin-2-yl)methoxy)-4-(piperazin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine(91 mg, 0.175 mmol, 52.1% yield) was taken forward as the crude. ES+APCIMS m/z 519.3 [M+H]⁺.

Step F:(S)-1-(4-(7-(3-(methoxymethoxy)naphthalen-1-yl)-2-((1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

To a suspension of(S)-7-(3-(methoxymethoxy)naphthalen-1-yl)-2-((1-methylpyrrolidin-2-yl)methoxy)-4-(piperazin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine(92 mg, 0.18 mmol) in dichloromethane (1774 μl, 0.18 mmol) at ambienttemperature was added Acryloyl Chloride (1774 μl, 0.18 mmol) followed byHunig's base (62 μl, 0.35 mmol). The reaction was then stirred atambient temperature for 1 hour. The mixture was then concentrated andloaded onto a 4 g RegiSep gold column and chromatographed on theCombiFlash (0%-15%, DCM:MeOH). All fractions containing clean productwere combined and concentrated in vacuo to give(S)-1-(4-(7-(3-(methoxymethoxy)naphthalen-1-yl)-2-((1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one(74 mg, 0.13 mmol, 73% yield). ES+APCI MS m/z 573.3 [M+H]⁺.

Step G:(S)-1-(4-(7-(3-hydroxynaphthalen-1-yl)-2-((1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

(S)-1-(4-(7-(3-(methoxymethoxy)naphthalen-1-yl)-2-((1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one(74 mg, 0.13 mmol) was dissolved in methanol (4307 μl, 0.13 mmol) andtreated with hydrogen chloride (1077 μl, 6.5 mmol) (aq). The reactionstirred at 55° C. for 1 hour. The reaction mixture was concentrated invacuo and was resuspended in 1.5 mL of MeOH. The suspension was loadedon to the Gilson (prep HPLC), which was eluted with 5->95% ACN/0.1% TFAin water/0.1% TFA. All fractions containing clean product were combinedand lyophilized overnight to give(S)-1-(4-(7-(3-hydroxynaphthalen-1-yl)-2-((1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one(26 mg, 0.049 mmol, 38% yield). ES+APCI MS m/z 529.3 [M+H]⁺.

Example 1281-(4-(2-(3-(dimethylamino)azetidin-1-yl)-7-(3-hydroxynaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Step A: benzyl4-(2-(3-(dimethylamino)azetidin-1-yl)-7-(3-(methoxymethoxy)naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate:To a solution of benzyl4-(2-chloro-7-(3-(methoxymethoxy)naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(0.20 g, 0.35 mmol) in dioxanes was added N,N-dimethylazetidin-3-aminehydrochloride (0.24 g, 1.7 mmol) and N-ethyl-N-isopropylpropan-2-amine(0.45 g, 3.5 mmol) and the reaction was heated to 80° C. for 72 hrs. Thereaction was concentrated in vacuo and the residue chromatographed using0->20% MeOH/DCM as eluent to give benzyl4-(2-(3-(dimethylamino)azetidin-1-yl)-7-(3-(methoxymethoxy)naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(0.25 g, 105%). ES+APCI MS m/z 638.3 [M+H]⁺.

1-(4-(2-(3-(dimethylamino)azetidin-1-yl)-7-(3-hydroxynaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-onewas made according to Example 127 substituting benzyl4-(2-(3-(dimethylamino)azetidin-1-yl)-7-(3-(methoxymethoxy)naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylatefor benzyl(S)-4-(7-(3-(methoxymethoxy)naphthalen-1-yl)-2-((1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylatein step E. ES+APCI MS m/z 514.2 [M+H]⁺.

Example 1291-[4-[7-(3-hydroxy-1-naphthyl)-2-[(1R)-1-[(2R)-1-methylpyrrolidin-2-yl]ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one

Step A: Tert-butyl (2R)-2-[(1R)-1-hydroxyethyl]pyrrolidine-1-carboxylate

A mixture of BH₃-Me₂S (10 M, 549 uL) and(3aS)-1-methyl-3,3-diphenyl-3a,4,5,6-tetrahydropyrrolo[1,2-c][1,3,2]oxazaborole(1.00 M, 844 uL) in THF (10 mL) was stirred at 15° C. for 1 hour. To themixture was added a solution of tert-butyl(2R)-2-acetylpyrrolidine-1-carboxylate (0.90 g, 4.22 mmol) in THE (10mL) and the mixture stirred at 15° C. for 1 hour. The mixture wasquenched by addition of methanol (2.00 mL) and the reaction concentratedunder vacuum. The residue was purified by column chromatography (SiO₂,petroleum ether/ether acetate=50/1-5/1) to give tert-butyl(2R)-2-[(1R)-1-hydroxyethyl]pyrrolidine-1-carboxylate (0.60 g, 2.79mmol, 66.0% yield) as a colorless oil. ¹H NMR (400 MHz, CD₃OD) 6=5.18(br s, 1H), 3.73 (dt, J=4.8, 8.0 Hz, 1H), 3.70-3.43 (m, 2H), 3.28 (td,J=6.64, 10.8 Hz, 1H), 1.96 (qd, J=7.2, 12.8 Hz, 1H), 1.89-1.68 (m, 2H),1.62 (br s, J=6.4 Hz, 1H), 1.47 (s, 9H), 1.15 (d, J=6.0 Hz, 3H)

Step B: benzyl4-[7-(3-benzyloxy-1-naphthyl)-2-[(1R)-1-[(2R)-1-tert-butoxycarbonylpyrrolidin-2-yl]ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate

To a solution of benzyl4-[7-(3-benzyloxy-1-naphthyl)-2-methylsulfinyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(0.70 g, 1.08 mmol) and tert-butyl(2R)-2-[(1R)-1-hydroxyethyl]pyrrolidine-1-carboxylate (349 mg, 1.62mmol) in THE (10 mL) was added t-BuONa (312 mg, 3.24 mmol) and themixture stirred at 10° C. for 1 hour. The mixture was diluted with water(10 mL) and the aqueous layer extracted with ethyl acetate (3×10 mL).The combined organics were washed brine (20 mL), dried over Na₂SO₄,filtered and concentrated under vacuum. The residue was purified bycolumn chromatography (SiO₂, petroleum ether/ether acetate=3/1) to givebenzyl4-[7-(3-benzyloxy-1-naphthyl)-2-[(1R)-1-[(2R)-1-tert-butoxycarbonylpyrrolidin-2-yl]ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(0.35 g, 412 umol, 38.1% yield) as a yellow solid. ES+APCI MS m/z 799.4[M+H].

Step C: benzyl4-[7-(3-benzyloxy-1-naphthyl)-2-[(1R)-1-[(2R)-pyrrolidin-2-yl]ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate

A mixture of benzyl4-[7-(3-benzyloxy-1-naphthyl)-2-[(1R)-1-[(2R)-1-tert-butoxycarbonylpyrrolidin-2-yl]ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(0.30 g, 375 umol) and TFA (642 mg, 5.63 mmol, 417 uL) indichloromethane (0.42 mL) was stirred at 10° C. for 1 hour. The mixturewas concentrated under vacuum to give benzyl4-[7-(3-benzyloxy-1-naphthyl)-2-[(1R)-1-[(2R)-pyrrolidin-2-yl]ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(305 mg) LCMS [M+1]: ES+APCI MS m/z 699.2 [M+H]⁺.

Step D: benzyl4-[7-(3-benzyloxy-1-naphthyl)-2-[(1R)-1-[(2R)-1-methylpyrrolidin-2-yl]ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate

A mixture ofbenzyl4-[7-(3-benzyloxy-1-naphthyl)-2-[(1R)-1-[(2R)-pyrrolidin-2-yl]ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(0.30 g, crude), formaldehyde (210 mg, 1.85 mmol, 192 uL, 37% water) andAcOH (22.16 mg, 369 umol, 21.1 uL) in methanol (3.00 mL) was stirred at15° C. for 0.5 hours. To the mixture was added NaBH₃CN (58.0 mg, 923umol) and the mixture stirred at 15° C. for 48 hours. The mixture wasquenched by addition of H₂O (5 mL) at 0° C., and the aqueous layerextracted with ether acetate (3×10 mL). The combined organics werewashed with brine (15.0 mL), dried over Na₂SO₄, filtered andconcentrated under vacuum. The residue was purified by reverse phaseflash [water (0.10% Formic Acid)/acetonitrile] to give benzyl4-[7-(3-benzyloxy-1-naphthyl)-2-[(1R)-1-[(2R)-1-methylpyrrolidin-2-yl]ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(0.10 g, 126 umol) as a yellow oil. ES+APCI MS m/z 713.4 [M+H]⁺.

Step E:4-[2-[(1R)-1-[(2R)-1-methylpyrrolidin-2-yl]ethoxy]-4-piperazin-1-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl]naphthalen-2-ol

Ammonia was bubbled into methanol (3 mL) at −78° C. for 30 minutes.benzyl4-[7-(3-benzyloxy-1-naphthyl)-2-[(1R)-1-[(2R)-1-methylpyrrolidin-2-yl]ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(0.09 g, 126 umol) and dry 10% Pd/C (0.10 g) were next added added andthe mixture stirred at 10° C. for 1 hour under H₂ (15 psi). The reactionwas filtered and the filtrate was concentrated under vacuum to give4-[2-[(1R)-1-[(2R)-1-methylpyrrolidin-2-yl]ethoxy]-4-piperazin-1-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl]naphthalen-2-ol(0.04 g, crude) as a yellow oil. ES+APCI MS m/z 489.2 [M+H]⁺.

Step F:1-[4-[7-(3-hydroxy-1-naphthyl)-2-[(1R)-1-[(2R)-1-methylpyrrolidin-2-yl]ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one

To a solution of 4-[2-[(1R)-1-[(2R)-1-methylpyrrolidin-2-yl]ethoxy]-4-piperazin-1-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl]naphthalen-2-ol(0.04 g) and Et3N (124 mg, 1.23 mmol, 171 uL) in DCM (2.00 mL) at −40°C. was added prop-2-enoyl prop-2-enoate (7.23 mg, 57.3 umol) and thereaction stirred at −40° C. for 0.5 h. The mixture was quenched byaddition of methanol (0.10 mL) and concentrated under vacuum. Theresidue was purified by prep-HPLC (column: Phenomenex Synergi C18150*25*10 um; mobile phase: [water (0.225% Formic Acid)-ACN]; B %:10%-37% over 10 minutes) to give1-[4-[7-(3-hydroxy-1-naphthyl)-2-[(1R)-1-[(2R)-1-methylpyrrolidin-2-yl]ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one(9.13 mg, 15.5 umol) as a yellow solid. ES+APCI MS m/z 543.4 [M+H]⁺.

Example 1301-(4-(7-(3-hydroxynaphthalen-1-yl)-2-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

1-(4-(7-(3-hydroxynaphthalen-1-yl)-2-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-onewas prepared following Example 129 substituting(3aR)-1-methyl-3,3-diphenyl-3a,4,5,6-tetrahydropyrrolo[1,2-c][1,3,2]oxazaborole for(3aS)-1-methyl-3,3-diphenyl-3a,4,5,6-tetrahydropyrrolo[1,2-c][1,3,2]oxazaborolein Step A while also substituting tert-butyl(2S)-2-acetylpyrrolidine-1-carboxylate for tert-butyl(2R)-2-acetylpyrrolidine-1-carboxylate in Step A. ES+APCI MS m/z 543.4[M+H]⁺.

Example 1311-[4-[2-[(1R)-2-[ethyl(methyl)amino]-1-methyl-ethoxy]-7-(3-hydroxy-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one

Step A: (2R)-1-[ethyl(methyl)amino]propan-2-ol

(2R)-2-methyloxirane (540 mg, 9.31 mmol, 651 uL) was added toN-methylethanamine (500 mg, 8.46 mmol, 725 uL) in MeOH (10 mL). Theresulting solution was stirred at 80° C. for 3 hours in a sealed tube.Upon completion, the mixture was concentrated under vacuum to give(2R)-[ethyl(methyl)amino]propan-2-ol (260 mg, crude) as a light yellowoil which was used directly in the next step without furtherpurification.

Step B: benzyl4-[7-(3-benzyloxy-1-naphthyl)-2-[(1R)-2-[ethyl(methyl)amino]-1-methyl-ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate

To a solution of (2R)-1-[ethyl(methyl)amino]propan-2-ol (217 mg, 1.85mmol) in toluene (20 mL) was added benzyl4-[7-(3-benzyloxy-1-naphthyl)-2-methylsulfinyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(400 mg, 617 umol), Pd₂(dba)₃ (56.6 mg, 61.8 umol), BINAP (76.9 mg, 124umol) and NaOtBu (178 mg, 1.85 mmol) and the mixture de-gassed with N₂for 15 minutes and then heated to 90° C. for 16 hours under N₂. Uponcompletion, the reaction mixture was filtered and the filtrateconcentrated under vacuum. The residue was purified by reversed-phasechromatography to give benzyl4-[7-(3-benzyloxy-1-naphthyl)-2-[(1R)-2-[ethyl(methyl)amino]-1-methyl-ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(110 mg, 153 umol, 24.8% yield, 97.5% purity). ES+APCI MS m/z 701.4[M+H]⁺.

Step C:4-[2-[(1R)-2-[ethyl(methyl)amino]-1-methyl-ethoxy]-4-piperazin-1-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl]naphthalen-2-ol

To a solution of benzyl4-[7-(3-benzyloxy-1-naphthyl)-2-[(1R)-2-[ethyl(methyl)amino]-1-methyl-ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(100 mg, 143 umol) in MeOH (3.00 mL) was added HCl/MeOH (4 M, 143 uL),followed by Pd(OH)₂/C (50 mg) under N₂. The suspension was degassedunder vacuum and purged with H₂ several times. The mixture was stirredunder H₂ (15 psi) at 40° C. for 4 hours. Upon completion, the reactionmixture was filtered and the filtrate concentrated to give4-[2-[(1R)-2-[ethyl(methyl)amino]-1-methyl-ethoxy]-4-piperazin-1-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl]naphthalen-2-ol(76.0 mg, 125 umol, 87.5% yield, 90.3% purity, 2 HCl) which was useddirectly in the next step without further purification. ES+APCI MS m/z477.2 [M+H]⁺.

Step D:1-[4-[2-[(1R)-2-[ethyl(methyl)amino]-1-methyl-ethoxy]-7-(3-hydroxy-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one

To a solution of4-[2-[(1R)-2-[ethyl(methyl)amino]-1-methyl-ethoxy]-4-piperazin-1-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl]naphthalen-2-ol(70 mg, 127 umol, 2 HCl) and DIEA (98.8 mg, 764 umol, 133 uL) in DCM(1.50 mL) was added prop-2-enoyl prop-2-enoate (12.9 mg, 102 umol)dropwise at −50° C. The mixture was stirred at −40 to −20° C. for 30minutes. Upon completion, the mixture was quenched by addition of MeOH(17.0 mg) and concentrated under vacuum. The residue was diluted withwater (1 mL) and extracted with DCM (3×6 mL). The organic layers weredried over Na₂SO₄ and concentrated under vacuum. The residue waspurified by prep-HPLC (column: Phenomenex Gemini 150*25 mm*10 um; mobilephase: [water (0.05% ammonia hydroxide v/v)-ACN]; B %: 48%-78%, 10 min)to give1-[4-[2-[(1R)-2-[ethyl(methyl)amino]-1-methyl-ethoxy]-7-(3-hydroxy-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one(9.23 mg, 17.2 umol, 13.5% yield, 98.7% purity) as a yellow solid.ES+APCI MS m/z 531.3 [M+H]⁺.

Example 1321-[4-[2-[(1-cyclohexylpyrrolidin-3-yl)methoxy]-7-(3-hydroxy-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one

Step A: 1-cyclohexylpyrrolidine-3-carboxylate

To a solution of methyl pyrrolidine-3-carboxylate (1.00 g, 6.04 mmol,HCl) and DIEA (780 mg, 6.04 mmol, 1.05 mL) was added cyclohexanone (652mg, 6.64 mmol, 686 uL) and HOAc (725 mg, 12.1 mmol, 691 uL) at 0° C. Thereaction mixture was stirred at 0° C. for 0.5 h. To the reaction mixturewas added NaBH(OAc)₃ (3.84 g, 18.12 mmol) in portions at 0° C. Thereaction mixture was stirred at 0 to 15° C. for 12 hours. Uponcompletion, the reaction mixture was quenched by addition of water (5mL) and organics concentrated under vacuum. The aqueous layer wasextracted with DCM (10 mL×2) and the pH adjusted with sat NaHCO₃ (10 mL)and Na₂CO₃ (2 mL) to pH>8. The organic layers were combined, dried overNa₂SO₄ and concentrated under vacuum. The residue was triturated withMTBE/Petroleum Ether (1:3, 20 mL) and the filtrate concentrated undervacuum to give methyl 1-cyclohexylpyrrolidine-3-carboxylate (1.00 g,4.73 mmol, 78.4% yield) as brown oil. ES+APCI MS m/z 212.2 [M+H]⁺.

Step B: (1-cyclohexylpyrrolidin-3-yl)methanol

To a solution of methyl 1-cyclohexylpyrrolidine-3-carboxylate (1.00 g,4.73 mmol) in THE (20 mL) was added LiAlH₄ (413 mg, 10.9 mmol) at −10°C. The reaction mixture was stirred at −10° C. for 0.5 hour. Thereaction mixture was quenched by addition of saturated Na₂SO₄ (2 mL) andmixture filtered and the filter cake washed with THE (3×50 mL). Thecombined organics were concentrated under vacuum to give:(1-cyclohexylpyrrolidin-3-yl)methanol (800 mg, 4.36 mmol, 92.3% yield)as a colorless oil. ¹H NMR (400 MHz, CHLOROFORM-d) 6=3.71 (dd, J=4.1,10.0 Hz, 1H), 3.53 (dd, J=4.4, 10.0 Hz, 1H), 2.90 (dt, J=4.4, 8.8 Hz,1H), 2.74 (dd, J=3.2, 8.8 Hz, 1H), 2.53 (dd, J=6.8, 8.8 Hz, 1H),2.36-2.24 (m, 2H), 2.04-1.93 (m, 2H), 1.90 (br s, 2H), 1.78-1.64 (m,3H), 1.61-1.52 (m, 1H), 1.33-1.12 (m, 5H) [0535]1-[4-[2-[(1-cyclohexylpyrrolidin-3-yl)methoxy]-7-(3-hydroxy-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-onewas prepared following Example 131 substituting(1-cyclohexylpyrrolidin-3-yl)methanol for(2R)-1-[ethyl(methyl)amino]propan-2-ol in Step B. ES+APCI MS m/z 597.4[M+H]⁺.

Example 1331-[4-[7-(3-hydroxy-1-naphthyl)-2-(3-morpholinopropylamino)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one

Step A: benzyl4-[7-(3-benzyloxy-1-naphthyl)-2-(3-morpholinopropylamino)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate:A solution of benzyl4-[7-(3-benzyloxy-1-naphthyl)-2-methylsulfinyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(400 mg, 617 umol) and 3-morpholinopropan-1-amine (534 mg, 3.70 mmol,540 uL) in DMSO (4.00 mL) was heated to 100° C. for 12 hours. Uponcompletion, the mixture was diluted with water (4 mL) and extracted withEtOAc (3×20 mL). The organic layers were washed with brine (30 mL),dried over Na₂SO₄ and concentrated under vacuum. The residue waspurified by column chromatography over Al₂O₃ eluting with EthylAcetate/Petroleum Ether (20→100%) to give benzyl4-[7-(3-benzyloxy-1-naphthyl)-2-(3-morpholinopropylamino)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(245 mg, 320 umol, 51.8% yield, 95.0% purity) as a yellow oil. ES+APCIMS m/z 728.6 [M+H]⁺.

1-[4-[7-(3-hydroxy-1-naphthyl)-2-(3-morpholinopropylamino)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-onewas prepared following Example 131 substituting benzyl4-[7-(3-benzyloxy-1-naphthyl)-2-(3-morpholinopropylamino)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylatefor benzyl4-[7-(3-benzyloxy-1-naphthyl)-2-[(1R)-2-[ethyl(methyl)amino]-1-methyl-ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylatein Step C. ES+APCI MS m/z 558.6 [M+H]⁺.

Example 134(R)-1-(4-(7-(3-hydroxynaphthalen-1-yl)-2-(piperidin-3-ylmethoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Step A: Tert-butyl (3R)-3-(hydroxymethyl)piperidine-1-carboxylate

TEA (1.76 g, 17.4 mmol, 2.42 mL) was added to a solution of[(3R)-3-piperidyl]methanol (1.0 g, 8.68 mmol) in THE (25.0 mL), followedby the addition of a solution of Boc20 (1.89 g, 8.68 mmol, 1.99 mL) inTHE (5 mL) at 15° C. The mixture was stirred at 15° C. for 12 hours. Thesolvent was removed under vacuum and the residue dissolved in ethylacetate (50 ml) and H₂O (30 mL). The solution was acidified with HCl (6M) to pH-6 and the layers separated. The organics were washed with brine(3×50 mL) and the combined organics concentrated to dryness to givetert-butyl (3R)-3-(hydroxymethyl)piperidine-1-carboxylate (1.68 g, 7.80mmol, 89.9% yield, 100% purity) as colorless crystals. ¹H NMR (400 MHz,chloroform-d) 6=3.73 (br s, 2H), 3.51 (br d, J=6.8 Hz, 2H), 3.05 (br s,2H), 1.83-1.71 (m, 2H), 1.62 (br s, 1H), 1.46 (s, 9H), 1.44-1.37 (m,1H), 1.35-1.22 (m, 1H).

Step B: benzyl4-[7-(3-benzyloxy-1-naphthyl)-2-[[(3R)-1-tert-butoxycarbonyl-3-piperidyl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate

To a solution of tert-butyl (3R)-3-(hydroxymethyl)piperidine-1-carboxylate (332 mg, 1.54 mmol) in THE (5 mL) was addedt-BuONa (223 mg, 2.32 mmol). A solution of benzyl4-[7-(3-benzyloxy-1-naphthyl)-2-methylsulfinyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(500 mg, 772 umol) in THE (5 mL) was next added and the mixture stirredat 0° C. for 1 hour. The reaction mixture was filtered and concentratedunder reduced pressure and the residue purified by column chromatographyeluting with Petroleum ether/Ethyl Acetate (10/1 to 3/1) to give benzyl4-[7-(3-benzyloxy-1-naphthyl)-2-[[(3R)-1-tert-butoxycarbonyl-3-piperidyl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(510 mg, 628 umol, 81.4% yield, 98.4% purity) as a white solid. ES+APCIMS m/z 799.4 [M+H]⁺.

Step C:Tert-butyl(3R)-3-[[7-(3-hydroxy-1-naphthyl)-4-piperazin-1-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-2-yl]oxymethyl]piperidine-1-carboxylate

A solution of benzyl4-[7-(3-benzyloxy-1-naphthyl)-2-[[(3R)-1-tert-butoxycarbonyl-3-piperidyl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(250 mg, 313 umol) in MeOH (5 mL) was purged with NH₃ (10%, w/w) andthen 10% Pd/C (50 mg) was added. The suspension was degassed undervacuum and the mixture stirred under H₂ (15 psi) at 15° C. for 12 hours.The reaction mixture was filtered and concentrated under reducedpressure to dryness to give tert-butyl(3R)-3-[[7-(3-hydroxy-1-naphthyl)-4-piperazin-1-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-2-yl]oxymethyl]piperidine-1-carboxylate(126 mg, 211 umol, 67.4% yield, 96.2% purity) as a colorless oil.ES+APCI MS m/z 575.5 [M+H]⁺.

Step D: Tert-butyl(3R)-3-[[7-(3-hydroxy-1-naphthyl)-4-(4-prop-2-enoylpiperazin-1-yl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-2-yl]oxymethyl]piperidine-1-carboxylate

To a solution of tert-butyl(3R)-3-[[7-(3-hydroxy-1-naphthyl)-4-piperazin-1-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-2-yl]oxymethyl]piperidine-1-carboxylate(126 mg, 219 umol) and TEA (33.3 mg, 329 umol, 45.8 uL) in DCM (5.0 mL)was added prop-2-enoyl prop-2-enoate (24.9 mg, 197 umol) dropwise at−40° C. and the reaction stirred for 30 minutes at −40° C. The reactionmixture was quenched by addition MeOH (0.5 mL) and concentrated todryness. The residue was dissolved into EtOAc (50 mL) and H₂O (20 mL).The resulting solution was acidified with HCl (1 M) to pH-6 and thelayers separated. The combined organics were dried over Na₂SO₄, filteredand concentrated under reduced pressure to givetert-butyl(3R)-3-[[7-(3-hydroxy-1-naphthyl)-4-(4-prop-2-enoylpiperazin-1-yl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-2-yl]oxymethyl]piperidine-1-carboxylate(120 mg, 172 umol, 78.5% yield, 90.2% purity) as a yellow oil, which wasused directly for next step without further purification. ES+APCI MS m/z629.6 [M+H]⁺.

Step E: 1-[4-[7-(3-hydroxy-1-naphthyl)-2-[[(3R)-3-piperidyl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one

To a solution oftert-butyl(3R)-3-[[7-(3-hydroxy-1-naphthyl)-4-(4-prop-2-enoylpiperazin-1-yl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-2-yl]oxymethyl]piperidine-1-carboxylate(120 mg, 191 umol) in DCM (3.0 mL) was added TFA (326 mg, 2.86 mmol, 212uL) at 0° C. The mixture was stirred at 15° C. for 2 hours under N₂atmosphere. The reaction mixture was basified with NH₃ (30% in water,three drops) and concentrated to dryness. The residue was purified byprep-HPLC (column: Phenomenex Synergi C18 150*25*10 um; mobilephase:[water (0.225% Formic Acid)-ACN]; B %: 5%-35%, 10 min) to give1-[4-[7-(3-hydroxy-1-naphthyl)-2-[[(3R)-3-piperidyl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one(24.5 mg, 38.9 umol, 20.4% yield) as a yellow solid. ES+APCI MS m/z529.4 [M+H]⁺.

Example 1351-[4-[2-[3-(4-acetylpiperazin-1-yl)propoxy]-7-(3-hydroxy-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one

Step A: 1-[4-(3-hydroxypropyl)piperazin-1-yl]ethanone

To a solution of 1-piperazin-1-ylethanone (2.00 g, 15.6 mmol) and K₂CO₃(4.31 g, 31.2 mmol) in CH3CN (50.0 mL) was added 3-bromopropan-1-ol(3.25 g, 23.4 mmol). The mixture was stirred at 80° C. for 5 hours. Thesolid was filtered and the filtrate was evaporated to give1-[4-(3-hydroxypropyl)piperazin-1-yl]ethanone (2.00 g, 10.7 mmol, 68.8%yield) as a colorless oil.

1-[4-[2-[3-(4-acetylpiperazin-1-yl)propoxy]-7-(3-hydroxy-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-onewas prepared following Example 131 substituting1-[4-(3-hydroxypropyl)piperazin-1-yl]ethanone for benzyl4-[7-(3-benzyloxy-1-naphthyl)-2-[(1R)-2-[ethyl(methyl)amino]-1-methyl-ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylatein Step C. ES+APCI MS m/z 600.3 [M+H]⁺.

Example 1361-[4-[7-(3-hydroxy-1-naphthyl)-2-[2-(3-methoxypyrrolidin-1-yl)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one

Step A: 2-(3-methoxypyrrolidin-1-yl)ethanol

To a solution of 3-methoxypyrrolidine (450 mg, 3.27 mmol, HCl) and2-bromoethanol (408 mg, 3.27 mmol) in CH3CN (10 mL) was added K₂CO₃(1.36 g, 9.81 mmol). The mixture was stirred at 80° C. for 3 hours. Thesolid was filtered and the filtrate was evaporated to give2-(3-methoxypyrrolidin-1-yl)ethanol (450 mg, 3.10 mmol, 94.8% yield) asa colorless oil.

Step B: benzyl4-[7-(3-benzyloxy-1-naphthyl)-2-[2-(3-methoxypyrrolidin-1-yl)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate

A mixture of benzyl4-[7-(3-benzyloxy-1-naphthyl)-2-methylsulfinyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(500 mg, 771 umol), 2-(3-methoxypyrrolidin-1-yl)ethanol (224 mg, 1.54mmol), and t-BuONa (222 mg, 2.32 mmol) in toluene (10 mL) was stirred at20° C. for 1 hour under N₂ atmosphere. The mixture was cooled to 0° C.and HCl (2M) was added until pH-7. The mixture was filtered and filtratewas concentrated in vacuum. The residue was purified by columnchromatography using 0-10% MeOH/DCM as eluent to give benzyl4-[7-(3-benzyloxy-1-naphthyl)-2-[2-(3-methoxypyrrolidin-1-yl)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(110 mg, 147.9 umol, 19.1% yield) ES+APCI MS m/z 729.2 [M+H]⁺.

1-[4-[7-(3-hydroxy-1-naphthyl)-2-[2-(3-methoxypyrrolidin-1-yl)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-onewas prepared following Example 131 substituting benzyl4-[7-(3-benzyloxy-1-naphthyl)-2-[2-(3-methoxypyrrolidin-1-yl)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylatefor benzyl4-[7-(3-benzyloxy-1-naphthyl)-2-[(1R)-2-[ethyl(methyl)amino]-1-methyl-ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylatein Step C. ES+APCI MS m/z 559.3 [M+H]⁺.

Example 1371-[4-[7-(3-hydroxy-1-naphthyl)-2-[3-(3-methoxypyrrolidin-1-yl)propoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one

Step A

(3-methoxypyrrolidin-1-yl)propan-1-ol: To a solution of3-methoxypyrrolidine (500 mg, 3.63 mmol, HCl) and 3-bromopropan-1-ol(505 mg, 3.63 mmol) in CH₃CN (10 mL) was added K₂CO₃ (1.51 g, 10.9mmol). The mixture was stirred at 20° C. for 5 hours. The solid wasfiltered and the filtrate was evaporated to give3-(3-methoxypyrrolidin-1-yl)propan-1-ol (540 mg, 3.39 mmol, 93.3%yield).

1-[4-[7-(3-hydroxy-1-naphthyl)-2-[3-(3-methoxypyrrolidin-1-yl)propoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-onewas prepared following Example 131 substituting(3-methoxypyrrolidin-1-yl)propan-1-ol for(2R)-1-[ethyl(methyl)amino]propan-2-ol in Step B. ES+APCI MS m/z 573.3[M+H]⁺.

Example 1381-[4-[2-[2-(3,3-difluoroazetidin-1-yl)ethoxy]-7-(3-hydroxy-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one

Step A: 2-(3,3-difluoroazetidin-1-yl)ethanol

To a solution of 3,3-difluoroazetidine (500 mg, 3.86 mmol, HC) and2-bromoethanol (482 mg, 3.86 mmol, 274 uL) in CH3CN (10 mL) was addedK₂CO₃ (1.60 g, 11.5 mmol) and the reaction stirred at 80° C. for 16hours. The reaction was filtered and the filtrate evaporated to give2-(3,3-difluoroazetidin-1-yl)ethanol (300 mg, 2.19 mmol, 56.7% yield).

1-[4-[2-[2-(3,3-difluoroazetidin-1-yl)ethoxy]-7-(3-hydroxy-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-onewas prepared following Example 131 substituting give2-(3,3-difluoroazetidin-1-yl)ethanol for(2R)-1-[ethyl(methyl)amino]propan-2-ol in Step B. ES+APCI MS m/z 551.4[M+H]⁺.

Example 1391-[4-[2-[2-(3,3-difluoropyrrolidin-1-yl)ethoxy]-7-(3-hydroxy-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one

Step A: Methyl 2-(3,3-difluoropyrrolidin-1-yl)acetate

To a suspension of methyl 2-bromoacetate (1.17 g, 7.67 mmol, 723 uL) inDCM (10 mL) cooled to 0° C. was added TEA (1.76 g, 17.4 mmol, 2.42 mL)and 3,3-difluoropyrrolidine (1.00 g, 6.97 mmol, HCl) and the reactionmixture stirred at 20° C. for 16 hours. The reaction was filtered andfiltrate was evaporated. The residue was purified by columnchromatography with 0.5%->20% MeOH/DCM as eluent to give methyl2-(3,3-difluoropyrrolidin-1-yl)acetate (580 mg, 3.24 mmol, 46.4% yield).¹H NMR (400 MHz, chloroform-d) 6=3.73 (s, 3H), 3.38 (s, 2H), 3.11 (t,J=13.6 Hz, 2H), 2.92 (t, J=6.8 Hz, 2H), 2.36-2.26 (m, 2H).

Step B: 2-(3,3-difluoropyrrolidin-1-yl)ethanol

To a solution of LiAlH₄ (184 mg, 4.86 mmol) in THE (5.0 mL) was added asolution of methyl 2-(3,3-difluoropyrrolidin-1-yl)acetate (580 mg, 3.24mmol) in THE (5.0 mL) dropwise at 0° C. The mixture was warmed to 20° C.and stirred for 3 hours. The mixture was quenched by addition ofsaturated aqueous sodium sulfate solution (1.50 mL). The reaction wasfiltered and the filtrated was concentrated under vacuum to give2-(3,3-difluoropyrrolidin-1-yl)ethanol (330 mg, 2.18 mmol, 67.4% yield)as a colourless oil. ¹H NMR (400 MHz, chloroform-d) 6=3.64 (t, J=5.2 Hz,2H), 2.97 (t, J=13.2 Hz, 2H), 2.82 (t, J=7.2 Hz, 2H), 2.68 (t, J=5.2 Hz,2H), 2.49 (br. s, 1H), 2.34-2.24 (m, 2H).

1-[4-[2-[2-(3,3-difluoropyrrolidin-1-yl)ethoxy]-7-(3-hydroxy-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-onewas prepared following Example 131 substituting2-(3,3-difluoropyrrolidin-1-yl)ethanol for(2R)-1-[ethyl(methyl)amino]propan-2-ol in Step B. ES+APCI MS m/z 565.3[M+H]⁺.

Example 1402-[3-[[7-(3-hydroxy-1-naphthyl)-4-(4-prop-2-enoylpiperazin-1-yl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-2-yl]oxymethyl]pyrrolidin-1-yl]-N,N-dimethyl-acetamide

Step A: Methyl1-[2-(dimethylamino)-2-oxo-ethyl]pyrrolidine-3-carboxylate

A solution of methyl pyrrolidine-3-carboxylate (1.00 g, 6.04 mmol, HCl)and NaHCO₃ (1.01 g, 12.1 mmol, 470 uL) in ACN (200.0 mL) was stirred at10° C. for 5 minutes. A solution of 2-bromo-N,N-dimethyl-acetamide (1.00g, 6.04 mmol) in ACN (5.00 mL) was next added at 10° C. and the reactionstirred at 10° C. for 6 hours followed by and stirring at 50° C. for 2hours. The mixture was filtered and solids washed with DCM (3×15 ml).The filtrate was concentrated under vacuum and the residue purified bycolumn chromatography using 0→10% MeOH/DCM as eluent to give methyl1-[2-(dimethylamino)-2-oxo-ethyl]pyrrolidine-3-carboxylate (480 mg, 2.02mmol, 33.4% yield).

Step B: 2-[3-(hydroxymethyl)pyrrolidin-1-yl]-N,N-dimethyl-acetamide

To a solution of methyl1-[2-(dimethylamino)-2-oxo-ethyl]pyrrolidine-3-carboxylate (500 mg, 2.33mmol) in THE (10 mL) was added LiAlH₄ (203 mg, 5.36 mmol) at −60° C. andthe reaction mixture stirred at −60° C. for 10 minutes. The reactionmixture was quenched by the addition of saturated Na₂SO₄ (0.4 mL) andthe slurry was filtered. The filter cake was washed with THE (3×50 mL)and the filtrate concentrated under vacuum to give2-[3-(hydroxymethyl)pyrrolidin-1-yl]-N,N-dimethyl-acetamide (400 mg,2.15 mmol, 92.2% yield) as a brown oil. ES+APCI MS m/z 187.1 [M+H]⁺.

Step C: benzyl4-[7-(3-benzyloxy-1-naphthyl)-2-[[1-[2-(dimethylamino)-2-oxo-ethyl]pyrrolidin-3-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate

A mixture of benzyl4-[7-(3-benzyloxy-1-naphthyl)-2-methylsulfinyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(500 mg, 772 umol),2-[3-(hydroxymethyl)pyrrolidin-1-yl]-N,N-dimethyl-acetamide (216 mg,1.16 mmol) and NaOBu-t (148 mg, 1.54 mmol) in toluene (10 mL) wasstirred at 15° C. for 15 minutes. The reaction mixture was purifieddirectly by silica gel chromatography using 20-100% EtOAc/PetroleumEther to give benzyl4-[7-(3-benzyloxy-1-naphthyl)-2-[[1-[2-(dimethylamino)-2-oxo-ethyl]pyrrolidin-3-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(310 mg, 395 umol, 51.1% yield, 98% purity) as a brown solid. ES+APCI MSm/z 770.4 [M+H]⁺.

2-[3-[[7-(3-hydroxy-1-naphthyl)-4-(4-prop-2-enoylpiperazin-1-yl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-2-yl]oxymethyl]pyrrolidin-1-yl]-N,N-dimethyl-acetamidewas prepared following Example 131 substituting benzyl4-[7-(3-benzyloxy-1-naphthyl)-2-[[1-[2-(dimethylamino)-2-oxo-ethyl]pyrrolidin-3-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylatefor benzyl4-[7-(3-benzyloxy-1-naphthyl)-2-[(1R)-2-[ethyl(methyl)amino]-1-methyl-ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylatein Step C. ES+APCI MS m/z 600.3 [M+H]⁺.

Example 1411-[4-[2-[[1-(2-hydroxyethyl)pyrrolidin-3-yl]methoxy]-7-(3-hydroxy-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one

Step A: Methyl pyrrolidine-3-carboxylate

To a solution of 1-(tert-butyl) 3-methyl pyrrolidine-1,3-dicarboxylate(10.0 g, 43.6 mmol) in DCM (50 mL) was added HCl/dioxane (4 M, 109 mL)at 0° C. and stirred at 0° C. for 1 hour. The mixture was concentratedunder vacuum to give methyl pyrrolidine-3-carboxylate (7.00 g, crude,HCl) as brown oil. ¹H NMR (400 MHz, methanol-d₄) δ=3.77 (s, 3H),3.56-3.53 (m, 2H), 3.41-3.37 (m, 3H), 2.40-2.24 (m, 2H).

Step B: Methyl 1-(2-benzyloxyethyl)pyrrolidine-3-carboxylate

A solution of methyl pyrrolidine-3-carboxylate (3.0 g, 18.1 mmol, HCl),Cs₂CO₃ (17.7 g, 54.3 mmol) and KI (301 mg, 1.81 mmol) in MeCN (60 mL)was stirred at 15° C. for 5 min. Then a solution of2-bromoethoxymethylbenzene (4.67 g, 21.7 mmol, 3.43 mL) in ACN (15 mL)was added to the mixture at 15° C. and stirred at 15° C. for 1 hour. Themixture was next warmed to 50° C. and stirred at 50° C. for 12 hours.The reaction mixture was filtered and the filter cake washed with DCM(3×30 mL) and the filtrate concentrated under vacuum. The residue waspurified by prep-HPLC (column: Phenomenex luna C18 250*50 mm*10 um;mobile phase: [water (0.1% TFA)-ACN]; B %: 10ACN %-40ACN %, 30 min 40%min) to give methyl 1-(2-benzyloxyethyl)pyrrolidine-3-carboxylate (1.48g, 5.06 mmol, 27.9% yield, 90.0% purity) as brown oil. ¹H NMR (400 MHz,chloroform-d) 6=7.36-7.28 (m, 5H), 4.56 (s, 2H), 3.70 (s, 3H), 3.61-3.58(t, J=6.0 Hz, 2H), 3.02-3.00 (m, 2H), 2.78-2.67 (m, 4H), 2.58-2.49 (m,1H), 2.11-2.08 (m, 2H)

Step C: (1-(2-(benzyloxy)ethyl)pyrrolidin-3-yl)methanol

To the solution of methyl 1-(2-benzyloxyethyl)pyrrolidine-3-carboxylate(1.38 g, 5.24 mmol) in THE (27 mL) was added LiAlH₄ (457 mg, 12 mmol) at−10° C. and stirred at −10° C. for 0.5 hour. The reaction mixture wasquenched by saturated Na₂SO₄ (1 mL) and filtered, the filter cake waswashed with THE (5×30 mL), the filtrate was concentrated under vacuum togive (1-(2-(benzyloxy)ethyl)pyrrolidin-3-yl)methanol (1.30 g, 3.31 mmol,63.3% yield, 60.0% purity) as brown oil. ES+APCI MS m/z 236.1 [M+H]⁺.

1-[4-[2-[[1-(2-hydroxyethyl)pyrrolidin-3-yl]methoxy]-7-(3-hydroxy-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-onewas prepared following Example 136 substituting(1-(2-(benzyloxy)ethyl)pyrrolidin-3-yl)methanol for2-(3-methoxypyrrolidin-1-yl)ethanol in Step B. ES+APCI MS m/z 559.3[M+H]⁺.

Example 1421-[4-[2-(2-hydroxyethoxy)-7-(3-hydroxy-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one

1-[4-[2-(2-hydroxyethoxy)-7-(3-hydroxy-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-onewas prepared following Example 136 substituting2-[tert-butyl(dimethyl)silyl]oxyethanol for2-(3-methoxypyrrolidin-1-yl)ethanol in Step B. ES+APCI MS m/z 476.2[M+H]⁺.

Example 1431-[4-[2-(2,3-dihydroxypropoxy)-7-(3-hydroxy-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one

1-[4-[2-(2,3-dihydroxypropoxy)-7-(3-hydroxy-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-onewas prepared following Example 136 substituting(2,2-dimethyl-1,3-dioxolan-4-yl)methanol for2-(3-methoxypyrrolidin-1-yl)ethanol in Step B. ES+APCI MS m/z 506.3[M+H]⁺.

Example 144(S)-1-(4-(7-(3-hydroxynaphthalen-1-yl)-2-((1-(2-methoxyethyl)pyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Step A: Tert-butyl (2S)-2-(benzyloxymethyl)pyrrolidine-1-carboxylate

To a slurry of NaH (2.38 g, 59.6 mmol, 60% purity) in THE (50 mL) wasadded a solution of tert-butyl(2S)-2-(hydroxymethyl)pyrrolidine-1-carboxylate (10 g, 49.69 mmol) inTHE (50 mL) at 0° C. and the mixture was stirred at 10° C. for 1 hour.Bromomethylbenzene (12.8 g, 74.5 mmol, 8.85 mL) was added dropwise at 0°C. and the mixture was stirred at 10° C. for 16 hours. The mixture wasquenched by addition of saturated aqueous ammonia chloride solution (20mL) and then diluted with ethyl acetate (200 mL) and water (100 mL). Theseparated organic layer was washed with water (100 mL) and brine (100mL), dried over sodium sulfate, filtered and concentrated under vacuum.The residue was purified by column chromatography over silica gel(petroleum ether/ethyl acetate 100/1 to 5/1) to give tert-butyl(2S)-2-(benzyloxymethyl)pyrrolidine-1-carboxylate (8.2 g, 28.06 mmol,56.5% yield, 99.7% purity) was obtained as a colorless oil. ES+APCI MSm/z 192.1 [M+H-Boc]⁺.

Step B: (2S)-2-(benzyloxymethyl)pyrrolidine

To a solution of tert-butyl(2S)-2-(benzyloxymethyl)pyrrolidine-1-carboxylate (8.2 g, 28.14 mmol) inCH2C2 (28 mL) was added TFA (43.1 g, 378 mmol, 28.0 mL) dropwise at 0°C. under nitrogen atmosphere. The mixture was stirred at 15° C. for 1hour. The mixture was concentrated under vacuum. The residue was dilutedwith dichloromethane (100 mL) and then washed with 1M aqueous sodiumhydroxide (10 mL) until the aqueous layer reached pH 10. The separatedorganic layer was washed with brine (2×20 mL), dried over sodiumsulfate, filtered and concentrated under vacuum to give(2S)-2-(benzyloxymethyl)pyrrolidine (4 g, 20.9 mmol, 74.3% yieldLCMSES+APCI MS m/z 192.2 [M+H]⁺.

Step C: (2S)-2-(benzyloxymethyl)-1-(2-methoxyethyl)pyrrolidine

A mixture of 1-bromo-2-methoxy-ethane (0.9 g, 6.48 mmol, 608 uL),(2S)-2-(benzyloxymethyl)pyrrolidine (1.24 g, 6.48 mmol) and K₂CO₃ (2.68g, 19.4 mmol) in CH3CN (20 mL) was stirred at 15° C. for 1 hours andthen at 78° C. for 12 hours. The mixture was diluted with ethyl acetate(50 mL) and water (50 mL). The separated organic layer was washed withbrine (1×50 mL), dried over sodium sulfate, filtered and concentratedunder vacuum. The residue was purified by column chromatography oversilica gel (ethyl acetate/dichloromethane/methanol 1/1/0 to 10/10/2) togive (2S)-2-(benzyloxymethyl)-1-(2-methoxyethyl)pyrrolidine (900 mg,3.61 mmol, 55.7% yield) as a colorless oil. ES+APCI MS m/z 250.2 [M+H]⁺.

Step D: (S)-(1-(2-methoxyethyl)pyrrolidin-2-yl)methanol

A solution of (2S)-2-(benzyloxymethyl)-1-(2-methoxyethyl)pyrrolidine(900 mg, 3.61 mmol) in MeOH (20 mL) was added 10% Pd/C (721.88 umol) andthe slurry stirred under H₂ (50 psi) at 10° C. for 16 hours. Thereaction was filtered and the filtrate concentrated under vacuum to give(S)-(1-(2-methoxyethyl)pyrrolidin-2-yl)methanol (450 mg, 2.83 mmol,78.30% yield).

Step E: Benzyl4-[7-(3-benzyloxy-1-naphthyl)-2-[[(2S)-1-(2-methoxyethyl)pyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate

A mixture of [(2S)-1-(2-methoxyethyl)pyrrolidin-2-yl]methanol (245 mg,1.54 mmol), benzyl4-[7-(3-benzyloxy-1-naphthyl)-2-methylsulfinyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(500 mg, 772 umol), and t-BuONa (223 mg, 2.32 mmol) in THF (5 mL) wasstirred at 20° C. for 0.5 hour under N₂ atmosphere. The reaction mixturewas poured into H₂O (30 mL) and the aqueous layer extracted with ethylacetate (3×30 mL). The combined organics were washed with brine (30 mL),dried over anhydrous Na₂SO₄ and concentrated under vacuum to give aresidue. The residue was purified by column chromatography (SiO₂,DCM/MeOH=300/1 to 10:1) to give Benzyl4-[7-(3-benzyloxy-1-naphthyl)-2-[[(2S)-1-(2-methoxyethyl)pyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(260 mg, 349 umol, 45.3% yield). ES+APCI MS m/z 743.4 [M+H].

Step F: Tert-Butyl4-[7-(3-hydroxy-1-naphthyl)-2-[[(2S)-1-(2-methoxyethyl)pyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate

To a solution of benzyl4-[7-(3-benzyloxy-1-naphthyl)-2-[[(2S)-1-(2-methoxyethyl)pyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(240 mg, 323 umol) and (Boc)₂O (141 mg, 646 umol, 148 uL) in MeOH (150mL) was added 10% Pd/C (100 mg) under N₂ atmosphere. The suspension wasdegassed and purged with H₂ 3 times. The mixture was stirred under H₂(15 PSI) at 40° C. for 12 hours. The reaction mixture was filtered andthe filtrate concentrated to give tert-Butyl4-[7-(3-hydroxy-1-naphthyl)-2-[[(2S)-1-(2-methoxyethyl)pyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(215 mg, crude). ES+APCI MS m/z 619.1 [M+H]⁺.

Step G:4-[2-[[(2S)-1-(2-methoxyethyl)pyrrolidin-2-yl]methoxy]-4-piperazin-1-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl]naphthalen-2-ol

To a solution of tert-butyl4-[7-(3-hydroxy-1-naphthyl)-2-[[(2S)-1-(2-methoxyethyl)pyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(215 mg, 347 umol) in DCM (500 uL) was added TFA (594 mg, 5.21 mmol, 385uL) and the mixture stirred at 15° C. for 1 hour. The mixture wasconcentrated under vacuum to give4-[2-[[(2S)-1-(2-methoxyethyl)pyrrolidin-2-yl]methoxy]-4-piperazin-1-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl]naphthalen-2-ol(219 mg, 346 umol). ES+APCI MS m/z 519.4 [M+H]⁺.

Step H:1-[4-[7-(3-hydroxy-1-naphthyl)-2-[[(2S)-1-(2-methoxyethyl)pyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one

To a mixture of 4-[2-[[(2S)-1-(2-methoxyethyl)pyrrolidin-2-yl]methoxy]-4-piperazin-1-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl]naphthalen-2-ol(219 mg, 346 umol) and DIEA (447 mg, 3.46 mmol, 603 uL) indichloromethane (4.00 mL) cooled to −40° C. was added a solution ofprop-2-enoyl prop-2-enoate (34.9 mg, 276.92 umol) in dichloromethane(1.00 mL) under a nitrogen atmosphere. The mixture was stirred at −40°C. for 1 hour. The reaction was quenched by addition of saturated NaHCO₃(2.00 mL) and the mixture poured into ice-water (20 mL) and extractedwith dichloromethane (20 mL×2). The combined organics were dried oversodium sulfate, filtered and concentrated in vacuo. The residue waspurified by prep-HPLC (column: Gemini 150*25 5u; mobile phase: [water(0.05% ammonia hydroxide v/v)-ACN]; B %: 32%-62%, 12 min) to give1-[4-[7-(3-hydroxy-1-naphthyl)-2-[[(2S)-1-(2-methoxyethyl)pyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one(27 mg, 46.7 umol). ES+APCI MS m/z 573.3 [M+H]⁺.

Example 1451-[4-[7-(3-hydroxy-1-naphthyl)-2-[[(2S)-1-isopropylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one

Step A: Benzyl4-[7-(3-benzyloxy-1-naphthyl)-2-[[(2S)-1-tert-butoxycarbonylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate

To a solution of tert-butyl (2S)-2-(hydroxymethyl)pyrrolidine-1-carboxylate (1.24 g, 6.17 mmol) and benzyl4-[7-(3-benzyloxy-1-naphthyl)-2-methylsulfinyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(2 g, 3.09 mmol) in THE (50 mL) was added t-BuONa (890 mg, 9.26 mmol)and the reaction stirred at 15° C. for 0.5 hour. The reaction mixturewas poured into H₂O (100 mL) and extracted with ethyl acetate (3×100mL). The combined organics were washed with brine (50 mL), dried overanhydrous Na₂SO₄ and concentrated under vacuum to give a residue. Theresidue was purified by column chromatography (SiO₂, Petroleumether/Ethyl acetate=100/1 to 1:1) to give Benzyl4-[7-(3-benzyloxy-1-naphthyl)-2-[[(2S)-1-tert-butoxycarbonylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(1.62 g, 2.02 mmol, 65.5% yield). ES+APCI MS m/z 785.6 [M+H]⁺.

Step B:(2S)-2-[[7-(3-hydroxy-1-naphthyl)-4-piperazin-1-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-2-yl]oxymethyl]pyrrolidine-1-carboxylate

NH₃ was bubbled into MeOH (50 mL) at 15° C. for 30 minutes. To thissolution was added benzyl4-[7-(3-benzyloxy-1-naphthyl)-2-[[(2S)-1-tert-butoxycarbonylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(1.6 g, 2.04 mmol) followed by dry 10% Pd/C (500 mg) under N₂. Thesuspension was degassed under vacuum and purged with H₂ several times.The mixture was stirred under H₂ (15 psi) at 40° C. for 1 hour. Themixture was then filtered and the filtrate concentrated under vacuum togive tert-butyl(2S)-2-[[7-(3-hydroxy-1-naphthyl)-4-piperazin-1-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-2-yl]oxymethyl]pyrrolidine-1-carboxylate(1.00 g, 1.78 mmol). ES+APCI MS m/z 561.5 [M+H]⁺.

Step C: Tert-butyl(2S)-2-[[7-(3-hydroxy-1-naphthyl)-4-[4-(2,2,2-trifluoroacetyl)piperazin-1-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-2-yl]oxymethyl]pyrrolidine-1-carboxylate

To a solution of tert-butyl(2S)-2-[[7-(3-hydroxy-1-naphthyl)-4-piperazin-1-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-2-yl]oxymethyl]pyrrolidine-1-carboxylate(800 mg, 1.43 mmol) in DCM (5.00 mL) at 0° C. was added TFAA (599 mg,2.85 mmol) and DIEA (737 mg, 5.71 mmol) and the reaction stirred at 0°C. for 0.5 hour. The reaction mixture was poured into H₂O (50 mL) andextracted with ethyl acetate (50 mL×3). The combined organics werewashed with brine (30 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated under vacuum to give tert-butyl(2S)-2-[[7-(3-hydroxy-1-naphthyl)-4-[4-(2,2,2-trifluoroacetyl)piperazin-1-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-2-yl]oxymethyl]pyrrolidine-1-carboxylate(1.5 g, crude). ES+APCI MS m/z 657.5 [M+H]⁺.

Step D:2,2,2-trifluoro-1-[4-[7-(3-hydroxy-1-naphthyl)-2-[[(2S)-pyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]ethanone

To a solution of tert-butyl(2S)-2-[[7-(3-hydroxy-1-naphthyl)-4-[4-(2,2,2-trifluoroacetyl)piperazin-1-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-2-yl]oxymethyl]pyrrolidine-1-carboxylate(300 mg, crude) in DCM (500 uL) was added TFA (521 mg, 4.57 mmol, 338uL) and the mixture stirred at 15° C. for 1 hour. The mixture wasconcentrated under vacuum to give2,2,2-trifluoro-1-[4-[7-(3-hydroxy-1-naphthyl)-2-[[(2S)-pyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]ethanone(306 mg). ES+APCI MS m/z 557.3 [M+H]⁺.

Step E:2,2,2-trifluoro-1-[4-[7-(3-hydroxy-1-naphthyl)-2-[[(2S)-1-isopropylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]ethanone

To a solution of acetone (132 mg, 2.28 mmol, 167 uL) and2,2,2-trifluoro-1-[4-[7-(3-hydroxy-1-naphthyl)-2-[[(2S)-pyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]ethanone(306 mg, crude, TFA) in MeOH (5.00 mL) was added AcOH (54.8 mg, 912umol, 52.2 uL) and NaBH₃CN (115 mg, 1.83 mmol) and the mixture stirredat 15° C. for 16 hours. The reaction mixture was diluted with H₂O (20mL) and extracted with ethyl acetate (20 mL×3). The combined organicswere washed with brine (10 mL), dried over Na₂SO₄, filtered andconcentrated under reduced pressure to give2,2,2-trifluoro-1-[4-[7-(3-hydroxy-1-naphthyl)-2-[[(2S)-1-isopropylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]ethanone(300 mg, crude). ES+APCI MS m/z 599.5 [M+H]⁺.

Step F:4-[2-[[(2S)-1-isopropylpyrrolidin-2-yl]methoxy]-4-piperazin-1-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl]naphthalen-2-ol

To a solution of2,2,2-trifluoro-1-[4-[7-(3-hydroxy-1-naphthyl)-2-[[(2S)-1-isopropylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]ethanone(300 mg, crude) in MeOH (10 mL) was added K₂CO₃ (346 mg, 2.51 mmol) andthe mixture stirred at 15° C. for 1 hour. The reaction mixture wasfiltered and the filtrate concentrated to give4-[2-[[(2S)-1-isopropylpyrrolidin-2-yl]methoxy]-4-piperazin-1-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl]naphthalen-2-ol(250 mg). ES+APCI MS m/z 503.3 [M+H]⁺.

Step G:1-[4-[7-(3-hydroxy-1-naphthyl)-2-[[(2S)-1-isopropylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one

To a mixture of4-[2-[[(2S)-1-isopropylpyrrolidin-2-yl]methoxy]-4-piperazin-1-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl]naphthalen-2-ol(250 mg, crude) and DIEA (643 mg, 4.97 mmol, 866 uL) in DCM (5.00 mL)cooled to −40° C. was added a solution of prop-2-enoyl prop-2-enoate(50.2 mg, 398 umol) in DCM (1 mL) under nitrogen atmosphere. The mixturewas stirred at −40° C. for 1 hour. The reaction was quenched by additionof saturated NaHCO₃ (2.00 mL). The mixture was poured into ice-water (20mL) and extracted with DCM (20 mL×2). The combined organics were driedover sodium sulfate, filtered and concentrated in vacuo. The residue waspurified by prep-HPLC (column: Phenomenex Gemini 150*25 mm*10 um; mobilephase: [water (0.05% ammonia hydroxide v/v)-ACN]; B %: 52%-78%, 12 min).1-[4-[7-(3-hydroxy-1-naphthyl)-2-[[(2S)-1-isopropylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one(10 mg, 17.6 umol). ES+APCI MS m/z 557.3 [M+H]⁺.

Example 1461-[4-[7-(3-hydroxy-1-naphthyl)-2-[[(3R)-pyrrolidin-3-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one

Step A: benzyl4-[7-(3-benzyloxy-1-naphthyl)-2-[[(3R)-1-tert-butoxycarbonylpyrrolidin-3-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate:A mixture of benzyl4-[7-(3-benzyloxy-1-naphthyl)-2-methylsulfinyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(0.50 g, 772 umol), tert-butyl(3R)-3-(hydroxymethyl)pyrrolidine-1-carboxylate (311 mg, 1.54 mmol) andt-BuONa (223 mg, 2.32 mmol) in THE (10 mL) was stirred at 20° C. for 1hour. The mixture was diluted with water (10 mL) and the aqueous layerextracted with ether acetate (3×20 mL). The combined organics werewashed with saturated sodium chloride (1×30 mL), dried over Na₂SO₄,filtered and concentrated under vacuum. The residue was purified bycolumn chromatography (SiO₂, petroleum ether/ether acetate=3/1) to givebenzyl4-[7-(3-benzyloxy-1-naphthyl)-2-[[(3R)-1-tert-butoxycarbonylpyrrolidin-3-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(0.40 g, 499 umol). ES+APCI MS m/z 785.2 [M+H]⁺.

Step B: tert-butyl(3R)-3-[[7-(3-hydroxy-1-naphthyl)-4-piperazin-1-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-2-yl]oxymethyl]pyrrolidine-1-carboxylate: NH₃ was bubbled intomethanol (10 mL) at −78° C. for 30 minutes. Benzyl4-[7-(3-benzyloxy-1-naphthyl)-2-[[(3R)-1-tert-butoxycarbonylpyrrolidin-3-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(0.25 g, 319 umol) and 10% Pd/C (0.10 g) were added into the mixture andstirred at 10° C. for 1 hour under H₂ (15 psi). The mixture was filteredand concentrated under vacuum to give tert-butyl(3R)-3-[[7-(3-hydroxy-1-naphthyl)-4-piperazin-1-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-2-yl]oxymethyl]pyrrolidine-1-carboxylate (0.17 g, 303 umol).ES+APCI MS m/z 561.3 [M+H]⁺.

Step C: tert-butyl(3R)-3-[[7-(3-hydroxy-1-naphthyl)-4-(4-prop-2-enoylpiperazin-1-yl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-2-yl]oxymethyl]pyrrolidine-1-carboxylate:To a solution of tert-butyl(3R)-3-[[7-(3-hydroxy-1-naphthyl)-4-piperazin-1-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-2-yl]oxymethyl]pyrrolidine-1-carboxylate(0.17 g, 303 umol) and Et3N (153 mg, 1.52 mmol, 211 uL) indichloromethane (4.00 mL) cooled to −40° C. was added prop-2-enoylprop-2-enoate (26.8 mg, 212 umol) and the mixture stirred at −40° C. for0.5 h. The mixture was quenched by addition of methanol (0.10 mL) andconcentrated under vacuum. The residue was purified by columnchromatography (Al₂O₃, dichloromethane/methane=10/1) to give tert-butyl(3R)-3-[[7-(3-hydroxy-1-naphthyl)-4-(4-prop-2-enoylpiperazin-1-yl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-2-yl]oxymethyl]pyrrolidine-1-carboxylate(0.12 g, 189 umol). ES+APCI MS m/z 615.5 [M+H]⁺.

Step D:1-[4-[7-(3-hydroxy-1-naphthyl)-2-[[(3R)-pyrrolidin-3-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one:A mixture of tert-butyl(3R)-3-[[7-(3-hydroxy-1-naphthyl)-4-(4-prop-2-enoylpiperazin-1-yl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-2-yl]oxymethyl]pyrrolidine-1-carboxylate(0.10 g, 163 umol) and TFA (278 mg, 2.44 mmol, 181 uL) indichloromethane (0.20 mL) was stirred at 10° C. for 1 hour. The mixturewas quenched by addition of NH₃.H₂O and the pH adjusted until the pH=7.The mixture was purified by prep-HPLC (column: Venusil XBP C8 150*25*10um; mobile phase: [water (0.225% Formic Acid)-ACN]; B %: 15%-45%, 10min) to give1-[4-[7-(3-hydroxy-1-naphthyl)-2-[[(3R)-pyrrolidin-3-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one(22.8 mg, 42.9 umol). ES+APCI MS m/z 515.4 [M+H]⁺.

Example 1472-[4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile

Step A: (Z) and (E)-4-bromobut-2-enenitrile

To a solution of but-3-enenitrile (98 g, 1.46 mol, 118 mL) intert-butanol (150 mL) and petroleum ether (575 mL) was added a solutionof Br₂ (233 g, 1.46 mol, 75.3 mL) in tert-butanol (150 mL) at 15° C. andthe reaction stirred for 30 minutes. To the reaction was next added anethanol solution of sodium ethoxide (100 g, 0.6 mol, 850 mL). Thereaction mixture was stirred for 2 hours at the 15° C. The reaction wasnext filtered and the filtrate concentrated under vacuum. The residuewas purified by column chromatography using 2→20% ethylacetate/petroleum ether as eluent to give a mixture of (Z) and(E)-4-bromobut-2-enenitrile (141 g, E/Z=2.5/1, crude) as a slight yellowoil. ¹H NMR (400 MHz, chloroform-d) (E), 6=6.79 (td, J=7.2, 16.0 Hz,1H), 5.63 (d, J=16.0 Hz, 1H), 4.00 (dd, J=1.2, 6.8 Hz, 2H); (Z), 6=6.66(td, J=8.0, 10.8 Hz, 1H), 5.44 (d, J=10.8 Hz, 1H), 4.16 (dd, J=0.8, 8.0Hz, 2H).

Step B: 2-(1,4-dibenzylpiperazin-2-yl)acetonitrile

To a mixture of N,N′-dibenzylethane-1,2-diamine (115 g, 480 mmol, 113mL) and TEA (97.0 g, 959 mmol, 133 mL) in toluene (1 L) was added4-bromobut-2-enenitrile (70 g, crude) dropwise at 0° C. and the reactionstirred at 15° C. for 12 hours. The reaction mixture was filtered andthe filtrate concentrated under reduced pressure. The residue waspurified by column chromatography using 5→50% EtOAc/Petroleum Ether aseluent to give 2-(1,4-dibenzylpiperazin-2-yl)acetonitrile (82 g, 240mmol, two steps 37% yield, 89.3% purity) as a slight yellow semisolid.ES+APCI MS m/z 306.3 [M+H]⁺. ¹H NMR (400 MHz, chloroform-d) 6=7.40-7.23(m, 10H), 3.85-3.76 (m, 1H), 3.54-3.44 (m, 3H), 3.07-2.96 (m, 1H),2.94-2.84 (m, 1H), 2.68-2.35 (m, 7H).

Step C

2-piperazin-2-ylacetonitrile: To a solution of2-(1,4-dibenzylpiperazin-2-yl)acetonitrile (164 g, 536 mmol) in DCE(1500 mL) was added 1-chloroethyl carbonochloridate (306 g, 2.14 mol)dropwise at 0° C. After addition, the reaction mixture was heated to 85°C. for approximately 48 hours. The dichloroethane was evaporated and theresidue was taken up in MeOH (1500 mL) and heated to 70° C. for 1 hour.The reaction mixture was concentrated under reduced pressure and thesolids triturated with MTBE (3×3 L) and the solids dried under reducedpressure to give 2-piperazin-2-ylacetonitrile. The crude product waspurified by recrystallization with Ethanol and water (8:1, v:v) to give2-piperazin-2-ylacetonitrile as an off-white solid (53 g, 428 mmol,40.0% yield, 96.4% purity, 2 HCl). ES+APCI MS m/z 126.2 [M+H]⁺. H NMR(400 MHz, D₂O) δ=4.01-3.96 (m, 1H), 3.81-3.67 (m, 3H), 3.46-3.27 (m,3H), 3.09 (d, J=6.0 HZ, 2H).

Step D:2-[4-(7-benzyl-2-chloro-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl]acetonitrile

To a mixture of7-benzyl-2,4-dichloro-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine (1.2 g,4.08 mmol) and 2-piperazin-2-ylacetonitrile (808 mg, 4.08 mmol, 2HCl) indioxane (24 mL) was added DIEA (2.64 g, 20.4 mmol, 3.55 mL). Thereaction mixture was stirred at 50° C. for 3 hours. Upon completion, thereaction mixture was diluted with water (50 mL) and the aqueous layerextracted with EtOAc (3×80 mL). The combined organic layers were washedwith brine (30 mL), dried over Na₂SO₄ and concentrated under vacuum togive2-[4-(7-benzyl-2-chloro-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl]acetonitrile(1.56 g, 4.07 mmol, 100% yield) as a brown solid.

Step E: Tert-butyl4-(7-benzyl-2-chloro-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate

To2-[4-(7-benzyl-2-chloro-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl]acetonitrile(1.56 g, 4.07 mmol) was added (Boc)₂O (9.50 g, 43.5 mmol, 10 mL) and themixture heated to 50° C. for 2 hours. Upon completion, the reactionmixture was purified by silica gel chromatography using 10-50%EtOAc/Petroleum Ether as eluent to give tert-butyl4-(7-benzyl-2-chloro-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate(1.2 g, 2.44 mmol, 59.9% yield, 98.3% purity) as brown solid. ES+APCI MSm/z 483.3 [M+H]⁺. ¹H NMR (400 MHz, CHLOROFORM-d) 6=7.39-7.27 (m, 5H),4.59 (br s, 1H), 4.06 (br d, J=13.6 Hz, 2H), 3.90 (br d, J=11.6 Hz, 1H),3.74-3.49 (m, 4H), 3.29 (dd, J=4.0, 13.6 Hz, 1H), 3.18 (br s, 1H),3.10-3.00 (m, 1H), 2.85-2.55 (m, 6H), 1.53-1.45 (m, 9H).

Step F: tert-butyl4-[7-benzyl-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(cyanomethyl)piperazine-1-carboxylate

To a solution of [(2S)-1-methylpyrrolidin-2-yl]methanol (655.74 mg, 5.69mmol, 676 uL in THE (25 mL) was added NaH (182 mg, 4.55 mmol, 60%purity) at 0° C. and the reaction mixture stirred at 0° C. for 0.5 h. Tothe mixture was added tert-butyl4-(7-benzyl-2-chloro-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate (1.1 g, 2.28 mmol) and the reaction mixturestirred at 70° C. for 12 hours in a sealed tube under N₂. Uponcompletion, the reaction mixture was quenched by addition of saturatedNH₄Cl (20 mL) and the aqueous layer extracted with EtOAc (2×50 mL). Thecombined organics were washed with brine (10 mL), dried over Na₂SO₄,filtered and concentrated under vacuum to give tert-butyl4-[7-benzyl-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(cyanomethyl)piperazine-1-carboxylate(1.1 g, 1.86 mmol, 81.7% yield, 95% purity) as a brown solid. ES+APCI MSm/z 562.4 [M+H]⁺.

Step G: Tert-butyl2-(cyanomethyl)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate

Ammonia was bubbled into MeOH (30 mL) for 5 minutes. To this solutionwas added tert-butyl4-[7-benzyl-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(cyanomethyl)piperazine-1-carboxylate(950 mg, 1.69 mmol) and 10% Pd/C (200 mg). The suspension was degassedunder vacuum and purged with H₂ several times and the mixture stirredunder H₂ (15 psi) at 40° C. for 9 hours. Upon completion, the reactionmixture was filtered and concentrated under vacuum. The residue waspurified by prep-HPLC (column: Phenomenex Synergi Max-RP 250*50 mm*10um; mobile phase: [water (0.225% Formic Acid)-ACN]; B %: 15%-40%, 30;58% min) to give tert-butyl2-(cyanomethyl)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(400 mg, 830 umol, 49.1% yield, 97.8% purity) was obtained as brown oil.ES+APCI MS m/z 472.4 [M+H]⁺. ¹H NMR (400 MHz, CHLOROFORM-d) 6=4.59 (brs, 1H), 4.43-4.28 (m, 1H), 4.18-4.09 (m, 1H), 4.07-3.90 (m, 4H),3.88-3.78 (m, 1H), 3.21 (br dd, J=3.2, 13.6 Hz, 2H), 3.16-3.05 (m, 2H),3.03-2.90 (m, 2H), 2.82-2.55 (m, 4H), 2.48 (s, 3H), 2.33-2.22 (m, 1H),2.11-2.00 (m, 1H), 1.91-1.62 (m, 4H), 1.51 (s, 9H).

Step H: tert-butyl2-(cyanomethyl)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate

To a solution of tert-butyl2-(cyanomethyl)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(150 mg, 318 umol), 1-bromonaphthalene (98.8 mg, 477 umol, 66.3 uL),Cs₂CO₃ (311 mg, 954 umol), and RuPhos (29.7 mg, 63.6 umol) in toluene (3mL) was added Pd₂(dba)₃ (29.1 mg, 31.8 umol) and the suspension wasdegassed under vacuum and purged with N₂ 3 times. The reaction mixturewas stirred at 100° C. for 12 hours. The mixture was partitioned betweenwater (10 mL) and EtOAc (20 mL) and the layers separated. The aqueouslayer was extracted subsequently with EtOAc (3×20 mL). The combinedorganics were washed with brine (20 mL), dried over anhydrous Na₂SO₄,filtered and concentrated under reduced pressure. The residue waspurified by reverse flash to give tert-butyl2-(cyanomethyl)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(70 mg, 111 umol, 35.0% yield, 95.0% purity) as brown solid. ES+APCI MSm/z 598.6 [M+H]⁺. ¹H NMR (400 MHz, chloroform-d) 6=8.21-8.20 (m, 1H),7.87-7.85 (m, 1H), 7.61-7.59 (d, J=8.0 Hz, 1H), 7.51-7.49 (m, 2H),7.45-7.41 (t, J=7.6 Hz, 1H), 7.15-7.13 (d, J=7.2 Hz, 1H), 4.63 (br s,1H), 4.46 (br s, 1H), 4.33-4.28 (m, 4H), 4.10-4.07 (m, 2H), 3.97-3.94(br d, J=11.6 Hz, 1H), 3.46 (br s, 1H), 3.31-3.27 (br d, J=14.0 Hz, 1H),3.07-3.01 (m, 2H), 2.77 (br s, 3H), 2.55 (br s, 3H), 2.35 (br s, 1H),1.82 (br s, 7H), 1.52 (s, 9H).

Step I:2-[4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile

To a solution of tert-butyl2-(cyanomethyl)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(60 mg, 100 umol) in DCM (0.1 mL) was added TFA (154 mg, 1.35 mmol, 0.1mL) at 15° C. and stirred at 15° C. for 1 hour. The reaction mixture wasconcentrated under vacuum to give2-[4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(50 mg) as brown oil.

Step J:2-[4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile

To a solution of2-[4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(50 mg, 81.8 umol, TFA) and DIEA (106 mg, 817 umol, 142 uL) in DCM (0.2mL) was added prop-2-enoyl prop-2-enoate (11.3 mg, 89.9 umol) at 0° C.and the reaction stirred at 0-15° C. for 1.5 hour. The reaction mixturewas concentrated under vacuum. The residue was purified by prep-HPLC(column: Phenomenex Synergi C18 150*30 mm*4 um; mobile phase: [water(0.225% Formic Acid)-ACN]; B %: 15%-45%, 10.5 min) to give2-[4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile(9.16 mg, 15.1 umol, 18.5% yield, 98.7% purity, Formate) as yellow oil.ES+APCI MS m/z 552.5 [M+H]⁺. ¹H NMR (400 MHz, chloroform-d) 6=8.45 (brs, 1H), 8.22-8.19 (m, 1H), 7.87-7.85 (m, 1H), 7.62-7.60 (d, J=8.0 Hz,1H), 7.51-7.49 (m, 2H), 7.45-7.43 (t, J=7.6 Hz, 1H), 7.15-7.13 (d, J=7.2Hz, 1H), 6.60 (br s, 1H), 6.42-6.38 (m, 1H), 5.84-5.82 (br d, J=10.8 Hz,1H), 5.08 (br s, 1H), 4.78-4.53 (br dd, J=6.8, 11.6 Hz, 2H), 4.42-4.40(m, 1H), 4.27 (br s, 2H), 4.21-4.18 (br d, J=14.0 Hz, 1H), 4.12-3.78 (brd, J=12.8 Hz, 2H), 3.68-3.07 (m, 7H), 3.05-2.84 (m, 3H), 2.77 (d, J=1.6Hz, 3H), 2.71-2.64 (m, 1H), 2.26-2.17 (m, 1H), 2.11-2.03 (m, 1H),2.02-1.88 (m, 2H).

Example 1482-[4-[7-(5-methyl-1H-indazol-4-yl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile

Step A: tert-butyl2-(cyanomethyl)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-7-(5-methyl-1-tetrahydropyran-2-yl-indazol-4-yl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate:To a solution of tert-butyl2-(cyanomethyl)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(200 mg, 424 umol), 4-bromo-5-methyl-1-tetrahydropyran-2-yl-indazole(188 mg, 636 umol), RuPhos (39.6 mg, 84.8 umol) and Cs₂CO₃ (414 mg, 1.27mmol) in toluene (6 mL) was added Pd₂(dba)₃ (38.8 mg, 42.4 umol) and thereaction stirred at 100° C. for 12 hours under N₂. Upon completion, themixture was purified directly by silica gel chromatography (PE:EtOAc=3:1to 0:1) to give tert-butyl2-(cyanomethyl)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-7-(5-methyl-1-tetrahydropyran-2-yl-indazol-4-yl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(120 mg, 149 umol, 35.1% yield, 85.0% purity) as a brown solid. ES+APCIMS m/z 686.6 [M+H]⁺. ¹H NMR (400 MHz, CHLOROFORM-d) 6=8.04 (d, J=2.0 Hz,1H), 7.33-7.29 (m, 2H), 5.70 (dd, J=2.4, 9.2 Hz, 1H), 4.62 (br s, 1H),4.39 (br s, 1H), 4.34-4.28 (m, 2H), 4.20-4.14 (m, 1H), 4.05 (br d,J=12.0 Hz, 2H), 3.91 (br d, J=12.4 Hz, 1H), 3.81-3.72 (m, 1H), 3.53 (brt, J=4.8 Hz, 2H), 3.27 (br d, J=10.8 Hz, 2H), 3.10 (br d, J=6.8 Hz, 1H),3.06-2.96 (m, 1H), 2.90-2.65 (m, 5H), 2.59 (br d, J=10.2 Hz, 1H), 2.50(s, 3H), 2.43 (s, 3H), 2.35-2.26 (m, 1H), 2.23-2.15 (m, 1H), 2.11 (br s,2H), 1.90-1.65 (m, 7H), 1.54 (s, 9H).

Step B:2-[4-[7-(5-methyl-1H-indazol-4-yl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile:To a solution of tert-butyl2-(cyanomethyl)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-7-(5-methyl-1-tetrahydropyran-2-yl-indazol-4-yl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(150 mg, 219 umol) in DCM (0.2 mL) was added TFA (616 mg, 5.40 mmol, 0.4mL) and the reaction mixture stirred at 15° C. for 12 hours. Uponcompletion, the solvent was removed under vacuum to give2-[4-[7-(5-methyl-1H-indazol-4-yl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(159 mg, 218 umol, 99.6% yield, 2TFA) as a red oil.

Step C:2-[4-[7-(5-methyl-1H-indazol-4-yl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile:To a solution of2-[4-[7-(5-methyl-1H-indazol-4-yl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(159 mg, 218 umol, 2TFA) and DIEA (366 mg, 2.83 mmol, 493 uL) in DCM (4mL) at −40° C. was added prop-2-enoyl prop-2-enoate (24.7 mg, 196 umol)and the reaction mixture was stirred at −20° C. for 1 hour. Uponcompletion, the reaction mixture was quenched by addition of water (2mL) and the aqueous layer separated and back extracted with DCM (2×10mL). The combined organics were concentrated under vacuum and theresidue purified by silica gel chromatography (DCM:MeOH=50:1 to 5:1)followed by purification by reverse prep HPCL (column: PhenomenexSynergi C18 150*25*10 um; mobile phase: [water (0.225% FormicAcid)-ACN]; B %: 4%-34% over 10 minutes) to give2-[4-[7-(5-methyl-1H-indazol-4-yl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile(1.77 mg, 3.10 umol). ES+APCI MS m/z 556.5 [M+H]⁺. ¹H NMR (400 MHz,CHLOROFORM-d) 6=8.00 (s, 1H), 7.18 (br s, 1H), 7.16-7.11 (m, 1H), 6.52(br s, 1H), 6.37-6.21 (m, 1H), 5.75 (br d, J=10.4 Hz, 1H), 4.99 (br s,1H), 4.67 (br dd, J=6.4, 11.6 Hz, 1H), 4.34 (br dd, J=3.9, 11.6 Hz, 1H),4.24 (s, 2H), 4.11 (br d, J=12.8 Hz, 1H), 3.94 (br s, 1H), 3.57-3.40 (m,4H), 3.29 (br d, J=13.8 Hz, 1H), 3.19 (br s, 1H), 3.02 (br dd, J=12.4,19.7 Hz, 2H), 2.87 (br dd, J=8.4, 16.4 Hz, 2H), 2.76-2.58 (m, 6H), 2.35(s, 3H), 2.22-2.10 (m, 1H), 2.01 (br d, J=8.4 Hz, 1H), 1.89 (br s, 2H).

Example 1492-[4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-7-[5-(trifluoromethyl)-1H-indazol-4-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile

Step A: tert-butyl 2-(cyanomethyl)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-7-[5-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)indazol-4-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate:tert-butyl 2-(cyanomethyl)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(130 mg, 276 umol),2-[[4-bromo-5-(trifluoromethyl)indazol-1-yl]methoxy]ethyl-trimethyl-silane(120 mg, 303 umol), Pd₂(dba)₃ (50.5 mg, 55.1 umol), RuPhos (51.5 mg, 110umol), Cs₂CO₃ (225 mg, 689 umol) in toluene (3.00 mL) was de-gassed withN₂ and then heated to 90° C. for 12 hours under N₂. Upon completion, themixture was filtered and the filtrate was concentrated. The residue waspurified by prep-TLC (EtOAc/MeOH 8/1) to give tert-butyl2-(cyanomethyl)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-7-[5-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)indazol-4-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(140 mg, 169 umol, 61.4% yield, 95.0% purity) as a yellow solid. ES+APCIMS m/z 786.3 [M+H]⁺.

Step B: 2-[4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-7-[5-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)indazol-4-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile:To a solution of tert-butyl2-(cyanomethyl)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-7-[5-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)indazol-4-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(140 mg, 178 umol) in DCM (3.00 mL) was added 2,6-dimethylpyridine (229mg, 2.14 mmol) and TMSOTf (238 mg, 1.07 mmol) at 0° C. The mixture wasstirred at 15° C. for 2 hours. Upon completion, the mixture was quenchedby addition of MeOH (0.5 mL) and concentrated under vacuum to give2-[4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-7-[5-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)indazol-4-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(200 mg, crude) as a yellow oil which was used directly in the next stepwithout further purification. ES+APCI MS m/z 686.6 [M+H]⁺.

Step C:2-[4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-7-[5-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)indazol-4-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile:To a solution of2-[4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-7-[5-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)indazol-4-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(122 mg, 178 umol) and DIEA (138 mg, 1.07 mmol, 186 uL) in DCM (3.00 mL)was added prop-2-enoyl prop-2-enoate (18.0 mg, 143 umol) dropwise at 0°C. The mixture was stirred at 20° C. for 1.5 hours. Upon completion, themixture was diluted with water (0.5 mL) and extracted with EtOAc (2×5mL). The organic layers were dried over Na₂SO₄ and concentrated undervacuum. The residue was purified by prep-TLC (EA/MeOH 10/1) andprep-HPLC (column: Boston pH-lex 150*25 10 um; mobile phase: [water(0.1% TFA)-ACN]; B %: 39%-69%, 10 min) to give2-[4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-7-[5-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)indazol-4-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile(54.0 mg, 43.8 umol). ES+APCI MS m/z 740.6 [M+H]⁺.

Step D:2-[4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-7-[5-(trifluoromethyl)-1H-indazol-4-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile:To a solution of2-[4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-7-[5-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)indazol-4-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile(20 mg, 27.0 umol) in DCM (60 uL) was added TFA (30.8 mg, 270 umol). Themixture was stirred at 20° C. for 1 hour. The reaction was not completeso additional TFA (30.8 mg) was added and the reaction stirred at 20° C.for an additional 0.5 hour. Upon completion, the pH or the mixture wasadjusted to 8 by addition of saturated aqueous NaHCO₃ (1 mL) and theaqueous layer extracted with EtOAc (2×5 mL). The combined organics werewashed with brine (3 mL), dried over Na₂SO₄ and concentrated undervacuum. The residue was diluted with MeOH (0.5 mL) and NH₃.H₂O (0.5 mL)added and the mixture stirred at 20° C. for 0.5 hour. The mixture waspurified by prep-HPLC (column: Phenomenex Synergi C18 150*30 mm*4 um;mobile phase: [water (0.225% Formic Acid)-ACN]; B %: 15%-45%, 10.5 min)to give2-[4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-7-[5-(trifluoromethyl)-1H-indazol-4-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile(2.68 mg, 3.99 umol) as a white solid. ES+APCI MS m/z 610.5 [M+H]⁺. ¹HNMR (400 MHz, chloroform-d) 6=8.22 (s, 1H), 7.68 (d, J=9.2 Hz, 1H), 7.45(d, J=8.8 Hz, 1H), 6.60 (br s, 1H), 6.45-6.35 (m, 1H), 5.84 (br d,J=11.2 Hz, 1H), 5.09 (br s, 1H), 4.71-4.60 (m, 1H), 4.42-4.27 (m, 3H),4.17 (br d, J=11.2 Hz, 1H), 4.01 (br d, J=12.4 Hz, 2H), 3.78-3.31 (m,5H), 3.23-3.03 (m, 2H), 3.02-2.75 (m, 4H), 2.71 (s, 3H), 2.66-2.57 (m,1H), 2.27-2.12 (m, 1H), 2.10-2.03 (m, 3H). ES+APCI MS m/z 610.1 [M+H]⁺.

Example 1502-(1-acryloyl-4-(2-(((R)-1-(dimethylamino)propan-2-yl)oxy)-7-(3-hydroxynaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

Step A: tert-Butyl4-[7-benzyl-2-[(1R)-2-(dimethylamino)-1-methyl-ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(cyanomethyl)piperazine-1-carboxylate:To a mixture of tert-butyl4-(7-benzyl-2-chloro-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate(500 mg, 1.04 mmol), (2R)-1-(dimethylamino)propan-2-ol (214 mg, 2.07mmol and sodium tert-butoxide (298 mg, 3.11 mmol) in toluene (20 mL) wasadded BINAP (129 mg, 207 umol) and Pd₂(dba)₃ (94.8 mg, 104 umol) and themixture was sparged with nitrogen followed by stirring at 90° C. for 5hr. The mixture was diluted with ethyl acetate (100 mL) and water (100mL) and the organic layer was separated and dried over sodium sulfate,filtered and concentrated under vacuum. The residue was purified byreversed phase flash chromatography [water (0.1% Formic Acidwater)/acetonitrile]. The desired fractions were collected andneutralized with saturated aqueous sodium carbonate solution (5 mL) andextracted with 10% MeOH/DCM (2×50 mL). The combined organics were driedover sodium sulfate, filtered and concentrated under vacuum to givetert-Butyl4-[7-benzyl-2-[(1R)-2-(dimethylamino)-1-methyl-ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(cyanomethyl)piperazine-1-carboxylate(300 mg, 480 umol) ES+APCI MS m/z 550.4 [M+H]⁺.

Step B: tert-butyl2-(cyanomethyl)-4-[2-[(1R)-2-(dimethylamino)-1-methyl-ethoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate:To a solution of tert-butyl4-[7-benzyl-2-[(1R)-2-(dimethylamino)-1-methyl-ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(cyanomethyl)piperazine-1-carboxylate(1.1 g, 2.00 mmol) in MeOH (10 mL) was added a solution of NH₃ (792 mg,46.5 mmol) in MeOH (3.96 g, 123.56 mmol, 5 mL), followed by 10% Pd/C(500 mg). The mixture was stirred at 40° C. for 12 hr under H₂ (15 psi).The reaction was filtered and the filtrate was concentrated underreduced pressure to dryness to give tert-butyl2-(cyanomethyl)-4-[2-[(1R)-2-(dimethylamino)-1-methyl-ethoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(756 mg, crude) was obtained as a yellow solid. ES+APCI MS m/z 460.3[M+H]⁺.

Step C: tert-butyl2-(cyanomethyl)-4-[2-[(1R)-2-(dimethylamino)-1-methyl-ethoxy]-7-[3-(2,2-dimethylpropanoyloxy)-1-naphthyl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate:A mixture of (4-bromo-2-naphthyl) 2,2-dimethylpropanoate (304 mg, 990umol), tert-butyl2-(cyanomethyl)-4-[2-[(1R)-2-(dimethylamino)-1-methyl-ethoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(350 mg, 761 umol), [2-(2-aminoethyl)phenyl]-chloro-palladium,dicyclohexyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphane (84.4 mg, 114umol) and Cs₂CO₃ (620 mg, 1.90 mmol in toluene (10 mL) was purged withN₂ 3 times and the mixture stirred at 70° C. for 16 hours under N₂atmosphere. The reaction mixture was poured into H₂O (50 mL) andextracted with ethyl acetate (50 mL×3). The combined organics werewashed with brine (30 mL), dried over anhydrous Na₂SO₄ and concentratedunder vacuum to give a residue. The residue was purified by reversedphase flash [water (0.1% formic acid)/acetonitrile] to give tert-butyl2-(cyanomethyl)-4-[2-[(1R)-2-(dimethylamino)-1-methyl-ethoxy]-7-[3-(2,2-dimethylpropanoyloxy)-1-naphthyl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(210 mg, 303 umol). ES+APCI MS m/z 686.4 [M+H]⁺.

Step D:[4-[4-[3-(cyanomethyl)piperazin-1-yl]-2-[(1R)-2-(dimethylamino)-1-methyl-ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl]-2-naphthyl]2,2-dimethylpropanoate: To a solution of tert-butyl2-(cyanomethyl)-4-[2-[(1R)-2-(dimethylamino)-1-methyl-ethoxy]-7-[3-(2,2-dimethylpropanoyloxy)-1-naphthyl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(210 mg, 306 umol) in dichloromethane (300 uL) was added TFA (523 mg,4.59 mmol, 340 uL) and the mixture stirred at 15° C. for 2 hours. Themixture was concentrated under vacuum to give[4-[4-[3-(cyanomethyl)piperazin-1-yl]-2-[(1R)-2-(dimethylamino)-1-methyl-ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl]-2-naphthyl]2,2-dimethylpropanoate(214 mg, 305 umol). ES+APCI MS m/z 586.4 [M+H]⁺.

Step E:[4-[4-[3-(cyanomethyl)-4-prop-2-enoyl-piperazin-1-yl]-2-[(1R)-2-(dimethylamino)-1-methyl-ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl]-2-naphthyl]2,2-dimethylpropanoate:To a mixture of[4-[4-[3-(cyanomethyl)piperazin-1-yl]-2-[(1R)-2-(dimethylamino)-1-methyl-ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl]-2-naphthyl]2,2-dimethylpropanoate(214 mg, 305 umol, TFA) and DIEA (395 mg, 3.06 mmol, 532 uL) indichloromethane (5.00 mL) cooled to −40° C. was added a solution ofprop-2-enoyl prop-2-enoate (38.6 mg, 305 umol) in dichloromethane (1.00mL) under nitrogen atmosphere. The mixture was warmed up to 0° C. andstirred for 1 hour. The mixture was concentrated under vacuum to give aresidue. The residue was purified by reversed phase flash [water (0.1%trifluoroacetic acid)acetonitrile] to give[4-[4-[3-(cyanomethyl)-4-prop-2-enoyl-piperazin-1-yl]-2-[(1R)-2-(dimethylamino)-1-methyl-ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl]-2-naphthyl]2,2-dimethylpropanoate (100 mg, 156 umol). ES+APCI MS m/z 640.7 [M+H]⁺.

Step F:2-[4-[2-[(1R)-2-(dimethylamino)-1-methyl-ethoxy]-7-(3-hydroxy-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile:To a solution of[4-[4-[3-(cyanomethyl)-4-prop-2-enoyl-piperazin-1-yl]-2-[(1R)-2-(dimethylamino)-1-methyl-ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl]-2-naphthyl]2,2-dimethylpropanoate (90 mg, 141 umol) in THF (500 uL) cooled to 0° C.was added NaOH (2 M, 281.34 uL) and the mixture stirred at 15° C. for 16hours. The pH of the mixture was adjusted to 7 by addition of a 20% withformic acid solution. The aqueous solution was next extracted withdichloromethane (3×10 mL). The combined organics were dried over Na₂SO₄,filtered and concentrated under vacuum. The residue was purified byprep-HPLC (column: Phenomenex Synergi C18 150*25*10 um; mobile phase:[water (0.225% Formic Acid)-ACN]; B %: 7%-37%, 10 min) to give2-[4-[2-[(1R)-2-(dimethylamino)-1-methyl-ethoxy]-7-(3-hydroxy-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile(5 mg, 8.82 umol, 6.27% yield, 98% purity) ES+APCI MS m/z 556.3 [M+H]⁺.¹H NMR (400 MHz, methanol-d₄) δ=8.54 (br s, 0.6H), 8.07 (d, J=8.4 Hz,1H), 7.63 (d, J=8.4 Hz, 1H), 7.37 (t, J=7.2 Hz, 1H), 7.30-7.21 (m, 1H),6.91-6.72 (m, 3H), 6.29 (br d, J=16.4 Hz, 1H), 5.84 (br d, J=11.2 Hz,1H), 5.48 (br s, 1H), 5.26-4.96 (m, 1H), 4.57 (br s, 1H), 4.24-4.09 (m,4H), 3.74-3.54 (m, 1H), 3.48 (m, 2H), 3.22 (m, 2H), 3.10-2.86 (m, 5H),2.78 (br d, J=14.4 Hz, 1H), 2.53 (br s, 6H), 1.37 (dd, J=2.0, 6.4 Hz,3H).

Example 1512-(1-acryloyl-4-(2-(((R)-1-(dimethylamino)propan-2-yl)oxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

(2-(1-acryloyl-4-(2-(((R)-1-(dimethylamino)propan-2-yl)oxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrilewas prepared following Example 150 substituting 1-bromonaphthalene for(4-bromo-2-naphthyl) 2,2-dimethylpropanoate in Step C and omitting StepF. ES+APCI MS m/z 540.3 [M+H]⁺. ¹H NMR (400 MHz, methanol-d₄) δ=8.51 (s,1H), 8.26-8.19 (m, 1H), 7.90-7.84 (m, 1H), 7.62 (d, J=8.0 Hz, 1H),7.53-7.47 (m, 2H), 7.46-7.39 (m, 1H), 7.25-7.18 (m, 1H), 6.82 (br s,1H), 6.30 (br d, J=17.2 Hz, 1H), 5.84 (br d, J=10.4 Hz, 1H), 5.62-5.53(m, 1H), 5.08 (br s, 1H), 4.70-4.39 (m, 1H), 4.26-4.11 (m, 4H),3.94-3.59 (m, 1H), 3.48-3.34 (m, 2H), 3.28-3.18 (m, 3H), 3.13-2.92 (s,5H), 2.79-2.61 (s, 6H), 1.48 (dd, J=2.0, 6.0 Hz, 3H).

Example 1522-[4-[2-[(1R)-2-(dimethylamino)-1-methyl-ethoxy]-7-(5-methyl-1H-indazol-4-yl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile

Step A: Tert-butyl2-(cyanomethyl)-4-[2-[(1R)-2-(dimethylamino)-1-methyl-ethoxy]-7-(5-methyl-1-tetrahydropyran-2-yl-indazol-4-yl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate:A mixture of tert-butyl2-(cyanomethyl)-4-[2-[(1R)-2-(dimethylamino)-1-methyl-ethoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(0.50 g, 1.09 mmol), 4-bromo-5-methyl-1-tetrahydropyran-2-yl-indazole(482 mg, 1.63 mmol), t-BuONa (314 mg, 3.26 mmol) and[2-(2-aminoethyl)phenyl]-chloro-palladium;dicyclohexyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphane (80.4 mg, 109umol) in toluene (30 mL) was stirred at 70° C. for 10 hours. The mixturewas diluted with water (10 mL) and the aqueous layer extracted withethyl acetate (3×20 mL). The organic layers were washed with saturatedsodium chloride solution (30 mL), dried over Na₂SO₄, filtered andconcentrated under vacuum. The residue was purified by reverse phaseflash [water (Formic Acid, 0.1%)/acetonitrile] to give tert-butyl2-(cyanomethyl)-4-[2-[(1R)-2-(dimethylamino)-1-methyl-ethoxy]-7-(5-methyl-1-tetrahydropyran-2-yl-indazol-4-yl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(0.40 g, 522 umol, 48.0% yield) as a yellow solid. ES+APCI MS m/z 674.3[M+H]⁺. ¹H NMR (400 MHz, chloroform-d) 6=8.03 (d, J=1.6 Hz, 1H),7.31-7.27 (m, 2H), 5.68 (dd, J=2.4, 9.6 Hz, 1H), 5.31 (br s, 1H), 4.61(br s, 1H), 4.28 (s, 2H), 4.08-3.94 (m, 3H), 3.86 (br d, J=11.6 Hz, 1H),3.79-3.71 (m, 1H), 3.52 (br t, J=4.8 Hz, 2H), 3.24 (br d, J=12.8 Hz,2H), 3.04-2.91 (m, 1H), 2.87-2.67 (m, 5H), 2.65-2.47 (m, 2H), 2.41 (s,3H), 2.32 (br s, 6H), 2.17 (br d, J=4.0 Hz, 1H), 2.09 (br s, 1H), 1.77(br t, J=10.8 Hz, 3H), 1.52 (s, 9H), 1.36 (d, J=6.0 Hz, 3H).

Step B:2-[4-[2-[(1R)-2-(dimethylamino)-1-methyl-ethoxy]-7-(5-methyl-1-tetrahydropyran-2-yl-indazol-4-yl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile:To a solution of tert-butyl2-(cyanomethyl)-4-[2-[(1R)-2-(dimethylamino)-1-methyl-ethoxy]-7-(5-methyl-1-tetrahydropyran-2-yl-indazol-4-yl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(0.38 g, 564 umol) in dichloromethane (10 mL) was added TMSOTf (752 mg,3.38 mmol) and 2,6-dimethylpyridine (725 mg, 6.77 mmol) at 0° C. and themixture stirred at 10° C. for 1 hour. The mixture was quenched byaddition of methanol (0.10 mL) and concentrated under vacuum. Theresidue was purified by reversed phase chromatography [water (FormicAcid, 0.1%)/acetonitrile]. The collected fractions were combined and thepH adjusted pH >7 by addition of saturated sodium bicarbonate solutionand the aqueous layer extracted with dichloromethane/methanol (10/1)(3×10 mL). The extracts were washed with saturated sodium chloridesolution (10 mL), dried over Na₂SO₄, filtered and concentrated undervacuum to give2-[4-[2-[(1R)-2-(dimethylamino)-1-methyl-ethoxy]-7-(5-methyl-1-tetrahydropyran-2-yl-indazol-4-yl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(0.30 g, crude) as a yellow solid. ES+APCI MS m/z 574.1 [M+H]⁺.

Step C:2-[4-[2-[(1R)-2-(dimethylamino)-1-methyl-ethoxy]-7-(5-methyl-1-tetrahydropyran-2-yl-indazol-4-yl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile:To a solution of2-[4-[2-[(1R)-2-(dimethylamino)-1-methyl-ethoxy]-7-(5-methyl-1-tetrahydropyran-2-yl-indazol-4-yl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(0.20 g, crude) and TEA (176 mg, 1.74 mmol, 243 uL) in dichloromethane(1.00 mL) was added prop-2-enoyl prop-2-enoate (44.0 mg, 349 umol) at 0°C. and the reaction stirred at 0° C. for 0.5 h. The mixture was quenchedby addition of methanol (0.10 mL) and concentrated under vacuum. Theresidue was purified by reversed phase flash [water (Formic Acid,0.1%)/acetonitrile]. The collected fractions were combined and the pHadjusted to pH >7 by addition of saturated sodium bicarbonate solutionand the aqueous layer extracted with dichloromethane/methanol (10/1)(3×5.00 mL). The extracts were washed with saturated sodium chloridesolution (1×10 mL), dried over Na₂SO₄, filtered and concentrated undervacuum to give2-[4-[2-[(1R)-2-(dimethylamino)-1-methyl-ethoxy]-7-(5-methyl-1-tetrahydropyran-2-yl-indazol-4-yl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile(0.10 g, 127 umol, two steps 36.6% yield) as a yellow solid. ES+APCI MSm/z 628.6 [M+H]⁺.

Step D:2-[4-[2-[(1R)-2-(dimethylamino)-1-methyl-ethoxy]-7-(5-methyl-1H-indazol-4-yl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile:A mixture of2-[4-[2-[(1R)-2-(dimethylamino)-1-methyl-ethoxy]-7-(5-methyl-1-tetrahydropyran-2-yl-indazol-4-yl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile(40 mg, 63.7 umol) and TsOH (1.10 mg, 6.37 umol) in acetonitrile (3 mL)was stirred at 90° C. for 1 hour. The mixture was quenched by additionof saturated sodium bicarbonate (2 mL) at 0° C. and concentrated undervacuum. The residue was purified by column chromatography (Al₂O₃,dichloromethane/methanol=5/1). The collected desired fractions wereconcentrated under vacuum to give white solid. The residue was purifiedby prep-HPLC (column: Phenomenex Gemini 150*25 mm*10 um; mobile phase:[water (10 mM NH₄HCO₃)-ACN]; B %: 35%-65%, 3 min) and (column: BostonGreen ODS 150*30 5u; mobile phase: [water (0.225% Formic Acid)-ACN]; B%: 15%-45%, 10 min). The desired fractions were pooled and lyophilizatedto give2-[4-[2-[(1R)-2-(dimethylamino)-1-methyl-ethoxy]-7-(5-methyl-1H-indazol-4-yl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile(2.99 mg, 5.50 umol). ES+APCI MS m/z 544.5 [M+H]⁺. ¹H NMR (400 MHz,chloroform-d) δ=8.36 (br s, 1H), 8.09 (s, 1H), 7.29 (br s, 1H),7.24-7.20 (m, 1H), 6.62 (br d, J=13.6 Hz, 1H), 6.47-6.24 (m, 1H), 5.83(br d, J=10.8 Hz, 1H), 5.50 (br s, 1H), 5.08 (br s, 1H), 4.60 (br s,1H), 4.31 (s, 2H), 4.12 (br d, J=14.4 Hz, 1H), 3.99 (br d, J=10.8 Hz,1H), 3.55 (br t, J=5.6 Hz, 2H), 3.42-3.29 (m, 1H), 3.10 (br s, 1H),3.00-2.68 (m, 7H), 2.49 (s, 6H), 2.43 (s, 3H), 1.39 (d, J=6.0 Hz, 3H).

Example 1532-[4-[7-(3-hydroxy-1-naphthyl)-2-[3-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]propoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile

Step A: tert-butyl2-(cyanomethyl)-4-[7-[3-(2,2-dimethylpropanoyloxy)-1-naphthyl]-2-[3-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]propoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate:To a solution of tert-butyl2-(cyanomethyl)-4-[7-[3-(2,2-dimethylpropanoyloxy)-1-naphthyl]-2-methylsulfinyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(500 mg, 773 umol) and3-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]propan-1-ol (219 mg,1.39 mmol) in toluene (10 mL) was added tBuONa (111 mg, 1.16 mmol) underN₂. The reaction mixture was stirred at 18° C. for 0.5 hour. Uponcompletion, the mixture was purified by silica gel chromatography(PE:EtOAc=3:1 to 0:1 then EA:MeOH=50:1 to 10:1) followed by reversedflash chromatography (50% to 90% MeCN in water, base condition) to givetert-butyl2-(cyanomethyl)-4-[7-[3-(2,2-dimethylpropanoyloxy)-1-naphthyl]-2-[3-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]propoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(120 mg, 156 umol, 20.5% yield, 97.9% purity) as a brown solid. ¹H NMR(400 MHz, CHLOROFORM-d) 6=8.19-8.12 (m, 1H), 7.83-7.77 (m, 1H),7.55-7.43 (m, 2H), 7.29 (d, J=1.6 Hz, 1H), 6.84 (d, J=2.0 Hz, 1H), 4.64(br s, 1H), 4.42-4.35 (m, 3H), 4.26 (br d, J=5.2 Hz, 2H), 4.12-4.03 (m,3H), 3.96 (br d, J=12.8 Hz, 1H), 3.62 (dd, J=1.6, 7.6 Hz, 1H), 3.50 (brs, 2H), 3.31 (br d, J=13.6 Hz, 3H), 3.11-2.97 (m, 2H), 2.94 (br d, J=8.8Hz, 1H), 2.89-2.69 (m, 5H), 2.54 (br d, J=9.8 Hz, 1H), 2.00-1.92 (m,2H), 1.90-1.83 (m, 1H), 1.73 (br d, J=10.0 Hz, 1H), 1.53 (s, 9H), 1.41(s, 9H)

Step B:4-[4-[3-(cyanomethyl)piperazin-1-yl]-2-[3-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]propoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl]-2-naphthyl]2,2-dimethylpropanoate: A solution of tert-butyl2-(cyanomethyl)-4-[7-[3-(2,2-dimethylpropanoyloxy)-1-naphthyl]-2-[3-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]propoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(120 mg, 162 umol) in TFA (370 mg, 3.24 mmol, 240 uL) was stirred at 18°C. for 1 hour. Upon completion, the solvent was removed under vacuum togive4-[4-[3-(cyanomethyl)piperazin-1-yl]-2-[3-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]propoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl]-2-naphthyl]2,2-dimethylpropanoate (140 mg, 161 umol, 99.5% yield, 2TFA) as brownoil.

Step C:[4-[4-[3-(cyanomethyl)-4-prop-2-enoyl-piperazin-1-yl]-2-[3-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]propoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl]-2-naphthyl]2,2-dimethylpropanoate: To a solution of[4-[4-[3-(cyanomethyl)piperazin-1-yl]-2-[3-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]propoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl]-2-naphthyl]2,2-dimethylpropanoate (140 mg, 161 umol) and DIEA (167 mg, 1.29 mmol,225 uL) in DCM (2 mL) was added prop-2-enoyl prop-2-enoate (30.5 mg, 242umol) at 0° C. The reaction mixture was stirred at 18° C. for 1 hour.Upon completion, the reaction mixture was quenched by addition of water(5 mL) and the aqueous layer extracted with DCM (3×10 mL). The combinedorganic layers were dried over Na₂SO₄, filtered and concentrated undervacuum. The residue was purified by reversed flash (Base condition,MeCN/NH₃.H₂O in water: 50% to 80%) to give[4-[4-[3-(cyanomethyl)-4-prop-2-enoyl-piperazin-1-yl]-2-[3-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]propoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl]-2-naphthyl]2,2-dimethylpropanoate (60 mg, 86.5 umol, 53.6% yield). ¹H NMR (400 MHz,CHLOROFORM-d) 6=8.22-8.13 (m, 1H), 7.84-7.78 (m, 1H), 7.56-7.45 (m, 2H),7.31 (d, J=2.0 Hz, 1H), 6.86 (d, J=2.4 Hz, 1H), 6.62 (br s, 1H),6.47-6.37 (m, 1H), 5.92-5.79 (m, 1H), 5.24-4.88 (m, 1H), 4.75 (br s,1H), 4.45-4.36 (m, 3H), 4.31-4.20 (m, 2H), 4.15 (br d, J=13.6 Hz, 1H),4.10-4.01 (m, 2H), 3.64 (dd, J=1.6, 7.6 Hz, 2H), 3.51 (br s, 2H), 3.38(br s, 2H), 3.14 (br s, 1H), 3.08-2.73 (m, 7H), 2.56 (br d, J=10.0 Hz,1H), 2.03-1.93 (m, 2H), 1.88 (br d, J=9.6 Hz, 1H), 1.78-1.70 (m, 1H),1.61 (s, 9H), 1.43 (s, 9H).

Step D:2-[4-[7-(3-hydroxy-1-naphthyl)-2-[3-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]propoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile:To a solution of[4-[4-[3-(cyanomethyl)-4-prop-2-enoyl-piperazin-1-yl]-2-[3-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]propoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl]-2-naphthyl]2,2-dimethylpropanoate (60 mg, 86.5 umol) in THE (0.5 mL) was added NaOH(2 M, 600 uL). The reaction mixture was stirred at 18° C. for 12 hours.Upon completion, the reaction mixture was acidified by addition of 4drops of HCOOH (20% in water) and the aqueous layer was extracted withDCM (5×8 mL). The combined organics were dried over Na₂SO₄ andconcentrated under vacuum. The residue was purified by prep-HPLC(column: Luna C18 150*25 5u; mobile phase: [water (0.225% FormicAcid)-ACN]; B %: 10%-40%, 10 min) to give2-[4-[7-(3-hydroxy-1-naphthyl)-2-[3-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]propoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile(19.8 mg, 28.3 umol, 32.8% yield, 93.8% purity, Formic Acid salt) wasobtained as a brown solid. ES+APCI MS m/z 610.5 [M+H]⁺.

Example 1542-[4-[7-(1-naphthyl)-2-[3-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]propoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile

Step A:tert-butyl2-(cyanomethyl)-4-[2-methylsulfanyl-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate:To the solution of tert-butyl2-(cyanomethyl)-4-(2-methylsulfanyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(3 g, 7.42 mmol), 1-bromonaphthalene (3.07 g, 14.8 mmol, 2.06 mL) andCs₂CO₃ (7.25 g, 22.2 mmol) in toluene (60 mL) was added XPhospalladacycle gen 3 (628 mg, 742 umol) under N₂ and the suspension wasdegassed under vacuum and purged with N₂ several times. The mixture waswarmed to 70° C. and stirred at 70° C. for 10 hours. The resultingmixture was filtered and the filter cake was washed with EtOAc (3×20mL). The combined organics were concentrated under reduced pressure togive a residue. The residue was purified by silica gel chromatography(PE:EtOAc from 50:1 to 3:1) to givetert-butyl2-(cyanomethyl)-4-[2-methylsulfanyl-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(3.55 g, 6.02 mmol, 81.2% yield, 90.0% purity) as brown oil. ES+APCI MSm/z 531.4 [M+H]⁺

Step B: tert-butyl2-(cyanomethyl)-4-[2-methylsulfinyl-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate:To the solution of tert-butyl2-(cyanomethyl)-4-[2-methylsulfanyl-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(2.95 g, 5.56 mmol) in DCM (60 mL) was added m-CPBA (1.13 g, 5.56 mmol,85.0% purity) at 0° C. and stirred at 0° C. for 1 hour. The reactionmixture was quenched by addition of saturated Na₂S₂O₃ (20 mL) at 0° C.and layers were separated, and the aqueous layer diluted with water (20mL) and extracted with EtOAc (60 mL). The combined organic layers weredried over anhydrous Na₂SO₄, filtered and concentrated under reducedpressure to give a residue. The residue was purified by reversed phaseflash column (ACN/Water (0.1% Formic Acid)=100%) to give tert-butyl2-(cyanomethyl)-4-[2-methylsulfinyl-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(1.7 g 2.80_mmol, 50.3 0 yield, 90.0% purity) as brown solid. ES+APCI MSm/z

Step C:tert-butyl2-(cyanomethyl)-4-[7-(1-naphthyl)-2-[3-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]propoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate:To a solution of tert-butyl2-(cyanomethyl)-4-[2-methylsulfinyl-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(300 mg, 549 umol) and3-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]propan-1-ol (160 mg,1.02 mmol) in toluene (6 mL) was added tBuONa (79.1 mg, 823 umol). Thereaction mixture was stirred at 18° C. for 0.5 hour. Upon completion,the reaction mixture was purified by silica gel chromatography(PE:EA=3:1 to 0:1 then EA:MeOH=50:1 to 10:1) to give tert-butyl2-(cyanomethyl)-4-[7-(1-naphthyl)-2-[3-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]propoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(200 mg, 249 umol, 45.3% yield, 79.6% purity) was obtained as a brownsolid. ES+APCI MS m/z 640.5 [M+H]⁺.

Step D:2-[4-[7-(1-naphthyl)-2-[3-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]propoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile:A reaction mixture of tert-butyl2-(cyanomethyl)-4-[7-(1-naphthyl)-2-[3-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]propoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(200 mg, 313 umol) in TFA (770 mg, 6.75 mmol, 500 uL) was stirred at 18°C. for 1 hour. Upon completion the solvent was removed under vacuum togive2-[4-[7-(1-naphthyl)-2-[3-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]propoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(271 mg, crude) as a brown oil.

Step E:2-[4-[7-(1-naphthyl)-2-[3-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]propoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile:To a solution of2-[4-[7-(1-naphthyl)-2-[3-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]propoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(271 mg, 502 umol) and DIEA (323 mg, 2.50 mmol, 0.435 mL) in DCM (6 mL)was added prop-2-enoyl prop-2-enoate (60 mg, 476 umol) at 0° C. and thereaction mixture stirred at 18° C. for 1 hour. Upon completion, thereaction mixture was quenched by addition of a drop of water andpurified by silica gel chromatography (PE:EtOAc=3:1 to 0:1) then prepHPLC (column: Gemini 150*25 5u; mobile phase: [water (0.05% ammoniahydroxide v/v)-ACN]; B %: 33%-63%, 12 min) to give2-[4-[7-(1-naphthyl)-2-[3-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]propoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile(23.8 mg, 40.0 umol, 7.97% yield) as yellow solid. ES+APCI MS m/z 594.5[M+H]⁺.

Example 155(S)-1-(4-(7-(5-methyl-1H-indazol-4-yl)-2-((1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Step A: tert-butyl4-[7-benzyl-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate

To a mixture of [(2S)-1-methylpyrrolidin-2-yl]methanol (4.15 g, 36.0mmol, 4.28 mL) in THF (100 mL) was added NaH (2.16 g, 54.06 mmol, 60%purity) in portions at 0° C. After the mixture was stirred at 0° C. for1 hour, a solution oftert-butyl4-(7-benzyl-2-chloro-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(8.0 g, 18.02 mmol) in THE (60 mL) was added and the mixture was stirredat 70° C. for 11 hours. After completion, the reaction mixture waspoured into aqueous NH₄Cl (160 mL), and the aqueous layer extracted withEtOAc (2×100 mL). The combined organics were dried over Na₂SO₄, filteredand concentrated in vacuo. The residue was purified by columnchromatography (SiO₂, Petroleum ether/Ethyl acetate=3/1 to Ethylacetate/Methanol=10:1) to give tert-butyl4-[7-benzyl-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(4.9 g, 8.70 mmol, 48.3% yield, 92.8% purity) as gray solid. ES+APCI MSm/z 523.2 [M+H]⁺

Step B: tert-butyl 4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate

To a mixture of tert-butyl4-[7-benzyl-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(2.20 g, 4.21 mmol) in MeOH (30 mL) was added Pd(OH)₂/C (700 mg, 10%purity) and the mixture was degassed under vacuum and purged with H₂several times and the reaction stirred at 40° C. for 12 hours under H₂(15 Psi). After completion, the reaction mixture was filtered throughcelite and the filtrate concentrated to give tert-butyl4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(1.80 g, 4.02 mmol, 95.6% yield, 96.7% purity) as black solid. ES+APCIMS m/z 433.1 [M+H]⁺.

Step C: tert-butyl4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-7-(5-methyl-1-tetrahydropyran-2-yl-indazol-4-yl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate

To a mixture of tert-butyl4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(200 mg, 462 umol) and 4-bromo-5-methyl-1-tetrahydropyran-2-yl-indazole(204 mg, 694 umol) in toluene (4 mL) was added Pd₂(dba)₃ (63.5 mg, 69.4umol), RuPhos (43.2 mg, 92.5 umol) and Cs₂CO₃ (301 mg, 925 umol) and themixture stirred at 110° C. for 12 hours under N₂. After completion, thereaction mixture was partitioned between water (10 mL) and EtOAc and thelayers separated. The aqueous layer was subsequently extracted withEtOAc (2×10 mL) and the combined organics were dried over Na₂SO₄,filtered and concentrated. The residue was purified by columnchromatography (SiO₂, Petroleum ether/Ethyl acetate=5/1 to Ethylacetate/MeOH=10/1) to give tert-butyl4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-7-(5-methyl-1-tetrahydropyran-2-yl-indazol-4-yl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(240 mg, 310 umol, 67.1% yield, 83.6% purity) as brown oil. ES+APCI MSm/z 647.6 [M+H]⁺.

Step D:7-(5-methyl-1H-indazol-4-yl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-4-piperazin-1-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine

To a mixture of tert-butyl4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-7-(5-methyl-1-tetrahydropyran-2-yl-indazol-4-yl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(240 mg, 371 umol) in DCM (1 mL) was added TFA (1.54 g, 13.5 mmol, 1 mL)and the mixture stirred at 15° C. for 1 hour. After completion, thereaction mixture was concentrated to give7-(5-methyl-1H-indazol-4-yl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-4-piperazin-1-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine(250 mg, 309 umol, 83.4% yield, 85.5% purity, 2TFA) as brown solid whichwas used for the next step without further purification. ES+APCI MS m/z463.4 [M+H]⁺.

Step E:1-[4-[7-(5-methyl-1H-indazol-4-yl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one

To a mixture of7-(5-methyl-1H-indazol-4-yl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-4-piperazin-1-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine(250 mg, 362 umol, 2TFA) in DCM (2 mL) was added DIEA (702 mg, 5.43mmol, 946 uL) and the mixture cooled to −50° C. Prop-2-enoylprop-2-enoate (36.5 mg, 289 umol) was added in portions to the reactionat −50° C. and the mixture stirred at −50° C. for 30 minutes. Aftercompletion, the reaction mixture was quenched by addition of MeOH (1 mL)and the mixture concentrated. The residue was taken up in DCM (10 mL)and the organics washed with H₂O (2×8 mL). The organics were dried overNa₂SO₄, filtered and concentrated. The residue was purified by prep-HPLC((Instrument: gx-1; Column: Phenomenex Gemini C18 250*50 mm*10 um;Condition: water (0.05% ammonia hydroxide v/v)-ACN; Begin B: 32; End B:62; Gradient Time (min): 12; 100% B Hold Time (min): 2; FlowRate(ml/min): 25) to give1-[4-[7-(5-methyl-1H-indazol-4-yl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one(48.6 mg, 92.9 umol, 25.7% yield, 98.7% purity) as yellow solid. ES+APCIMS m/z 517.5 [M+H]⁺.

Example 156(S)-1-(4-(2-((1-methylpyrrolidin-2-yl)methoxy)-7-(5-(trifluoromethyl)-1H-indazol-4-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

(S)-1-(4-(2-((1-methylpyrrolidin-2-yl)methoxy)-7-(5-(trifluoromethyl)-1H-indazol-4-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-onewas prepared following Example 155 substituting4-bromo-1-tetrahydropyran-2-yl-5-(trifluoromethyl)indazole (Intermediate60) for 4-bromo-5-methyl-1-tetrahydropyran-2-yl-indazole in Step C.ES+APCI MS m/z 571.4 [M+H]⁺.

Example 157(S)-1-(4-(7-(5-methoxy-1H-indazol-4-yl)-2-((1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

(S)-1-(4-(7-(5-methoxy-1H-indazol-4-yl)-2-((1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-onewas prepared following Example 155 substituting4-bromo-5-methoxy-1-tetrahydropyran-2-yl-indazole for4-bromo-5-methyl-1-tetrahydropyran-2-yl-indazole in Step C. ES+APCI MSm/z 533.4 [M+H]⁺.

Example 1581-[4-[7-(2-isopropylphenyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one

Step A: tert-butyl4-[7-(2-isopropylphenyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate:tert-butyl4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(200 mg, 462 umol), 1-bromo-2-isopropyl-benzene (120 mg, 601 umol),Cs₂CO₃ (452 mg, 1.39 mmol) and XPHOS PALLADACYCLE GEN 3 (78.3 mg, 92.5umol) in toluene (4.00 mL) was de-gassed with N₂ and then heated to 100°C. for 10 hours under N₂. Upon completion, the mixture was filtered andthe filtrate was concentrated. The crude product was purified by silicagel chromatography eluted with EtOAc/MeOH=50/1 to 5/1 to give tert-butyl4-[7-(2-isopropylphenyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(84.6 mg, 134 umol, 28.9% yield, 87.0% purity) as a yellow solid.ES+APCI MS m/z 551.2 [M+H]⁺. [0629]1-[4-[7-(2-isopropylphenyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-onewas prepared following Example 155 substituting tert-butyl4-[7-(2-isopropylphenyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylatefor tert-butyl4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-7-(5-methyl-1-tetrahydropyran-2-yl-indazol-4-yl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylatein Step D. ES+APCI MS m/z 505.6 [M+H]⁺.

Example 159(S)-1-(4-(2-((1-methylpyrrolidin-2-yl)methoxy)-7-(2-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

(S)-1-(4-(2-((1-methylpyrrolidin-2-yl)methoxy)-7-(2-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-onewas prepared following Example 155 substituting1-bromo-2-(trifluoromethyl)benzene for4-bromo-5-methyl-1-tetrahydropyran-2-yl-indazole in Step C. ES+APCI MSm/z 531.5 [M+H]⁺.

Example 1601-(4-(7-(5-methyl-1H-indazol-4-yl)-2-(3-(piperidin-1-yl)propoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Step A: Benzyl4-[2-methylsulfanyl-7-[5-methyl-1-(2-trimethylsilylethoxymethyl)indazol-4-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate

A mixture of benzyl 4-(2-methylsulfanyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate (3.15 g, 7.88 mmol),2-[(4-bromo-5-methyl-indazol-1-yl)methoxy]ethyl-trimethyl-silane (3.50g, 10.2 mmol), Cs₂CO₃ (6.42 g, 19.70 mmol), Pd₂(dba)₃ (1.08 g, 1.18mmol) and RuPhos (735 mg, 1.58 mmol) in toluene (50 mL) was degassed andwith N₂ 3 times and the mixture stirred at 90° C. for 10 hours under N₂atmosphere. The reaction mixture was quenched by addition of water (100mL) and the aqueous layer extracted with ethyl acetate (3×100 mL). Thecombined organics were washed with brine (50 mL), dried over Na₂SO₄,filtered and concentrated under reduced. The residue was purified bycolumn chromatography using 1-33% EtOAc/Petroleum Ether to give benzyl4-[2-methylsulfanyl-7-[5-methyl-1-(2-trimethylsilylethoxymethyl)indazol-4-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(2.30 g, 2.93 mmol, 37.1% yield). ES+APCI MS m/z 660.3 [M+H]⁺.

Step B: benzyl 4-[2-methylsulfinyl-7-[5-methyl-1-(2-trimethylsilylethoxymethyl)indazol-4-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate

To a stirred solution of benzyl4-[2-methylsulfanyl-7-[5-methyl-1-(2-trimethylsilylethoxymethyl)indazol-4-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(2.30 g, 3.49 mmol) in DCM (20 mL) was added m-CPBA (601 mg, 3.49 mmol)at 0° C. The reaction mixture was stirred at 0° C. for 1 hour under N₂atmosphere. The reaction mixture was quenched by addition Na₂S₂O₃ (10mL) at 0° C., and then diluted with water (100 mL) and the aqueous layerextracted with DCM (200 mL). The combined organics were washed withbrine (200 mL), dried over Na₂SO₄, filtered and concentrated underreduced pressure. The residue was purified by column chromatographyusing 1410% MeOH/DCM as eluent to give benzyl4-[2-methylsulfinyl-7-[5-methyl-1-(2-trimethylsilylethoxymethyl)indazol-4-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(2.00 g, 2.84 mmol, 81.4% yield). ES+APCI MS m/z 676.3 [M+H]⁺.

Step C: benzyl4-[7-[5-methyl-1-(2-trimethylsilylethoxymethyl)indazol-4-yl]-2-[3-(1-piperidyl)propoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate

To a mixture of benzyl4-[2-methylsulfinyl-7-[5-methyl-1-(2-trimethylsilylethoxymethyl)indazol-4-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(500 mg, 739 umol) and 3-(1-piperidyl)propan-1-ol (211 mg, 1.48 mmol) inTHE (10 mL) was added t-BuONa (213 mg, 2.22 mmol) portion wise and themixture stirred at 20° C. for 1 hour under N₂ atmosphere. The mixturewas cooled to 0° C. and HCl (2M) was added until the pH-7. The mixturewas filtered and filtrate was concentrated in vacuo. The residue waspurified by reversed phase flash using water 5495% 0.5%TFA/water/acetonitrile as eluent to give benzyl4-[7-[5-methyl-1-(2-trimethylsilylethoxymethyl)indazol-4-yl]-2-[3-(1-piperidyl)propoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(300 mg, 385. umol, 52.1% yield). ES+APCI MS m/z 755.4 [M+H]⁺.

Step D:7-(5-methyl-1H-indazol-4-yl)-4-(piperazin-1-yl)-2-(3-(piperidin-1-yl)propoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine

To a solution of benzyl 4-[7-[5-methyl-1-(2-trimethylsilylethoxymethyl)indazol-4-yl]-2-[3-(1-piperidyl)propoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(300 mg, 397 umol) in MeOH (20 mL) was added HCl/MeOH (4 M, 1.99 mL) andPd(OH)₂ (200 mg, 10% purity) under N₂. The suspension was degassed undervacuum and purged with H₂ several times. The mixture was stirred underH₂ (15 psi) at 25° C. for 1 hour. The reaction mixture was filtered andthe filtrate was concentrated to give7-(5-methyl-1H-indazol-4-yl)-4-(piperazin-1-yl)-2-(3-(piperidin-1-yl)propoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine(250 mg, 360 umol, 90.7% yield).

Step E:1-[4-[7-(5-methyl-1H-indazol-4-yl)-2-[3-(1-piperidyl)propoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one

To a mixture of7-(5-methyl-1H-indazol-4-yl)-4-(piperazin-1-yl)-2-(3-(piperidin-1-yl)propoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine(250 mg, 360 umol, 2HCl) and DIA (465 mg, 3.60 mmol, 629 uL) in DCM(8.00 mL) was added a solution of prop-2-enoyl-prop-2-enoate (36.3 mg,288 umol) in DCM (2.00 mL) at −40° C. under nitrogen atmosphere and thereaction stirred for 1 hour. The reaction mixture was quenched byaddition NaHCO₃ (500 uL) at −40° C., and then diluted with water (10 mL)and the aqueous layer extracted with DCM (10 ml). The organics weredried over Na₂SO₄, filtered and concentrated under reduced pressure. Theresidue was purified by column chromatography (SiO₂, DCM/MeOH I/O to5/1) and further purified by prep-HPLC (column: Phenomenex Synergi C18150*25*10 um; mobile phase: [water (0.225% Formic Acid)-ACN]; B %:8%-28%, 10 min) to give1-[4-[7-(5-methyl-1H-indazol-4-yl)-2-[3-(1-piperidyl)propoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one(16.0 mg, 29.1 umol, 8.07% yield). ES+APCI MS m/z 545.3 [M+H]⁺.

Example 1611-[4-[7-(5-methyl-1H-indazol-4-yl)-2-[(1-methylpyrrolidin-3-yl)methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one

1-[4-[7-(5-methyl-1H-indazol-4-yl)-2-[(1-methylpyrrolidin-3-yl)methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-onewas prepared following Example 160 substituting(1-methylpyrrolidin-3-yl)methanol for 3-(1-piperidyl)propan-1-ol in StepC. ES+APCI MS m/z 517.4 [M+H]⁺.

Example 1621-[4-[2-[(1R)-2-(dimethylamino)-1-methyl-ethoxy]-7-(5-methyl-1H-indazol-4-yl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one

Step A: benzyl4-[2-[(1R)-2-(dimethylamino)-1-methyl-ethoxy]-7-[5-methyl-1-(2-trimethylsilylethoxymethyl)indazol-4-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate:A mixture of (2R)-1-(dimethylamino)propan-2-ol (183 mg, 1.78 mmol) (8.00mL), benzyl4-[2-methylsulfinyl-7-[5-methyl-1-(2-trimethylsilylethoxymethyl)indazol-4-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(400 mg, 592 umol) and NaOtBu (114 mg, 1.18 mmol) in toluene werestirred at 15° C. for 0.5 hour. The reaction mixture was filtered andthe filtrate was concentrated under vacuum. The residue was purified bycolumn chromatography over Al₂O₃ (Petroleum Ether/Ethyl Acetate 10/1 to0/1) to give benzyl4-[2-[(1R)-2-(dimethylamino)-1-methyl-ethoxy]-7-[5-methyl-1-(2-trimethylsilylethoxymethyl)indazol-4-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(280 mg, 352 umol). ¹H NMR (400 MHz, chloroform-d) 6=8.08 (s, 1H),7.46-7.39 (m, 5H), 7.38-7.33 (m, 2H), 5.76 (s, 2H), 5.43-5.33 (m, 1H),5.24 (s, 2H), 4.35 (s, 2H), 3.72-3.67 (m, 4H), 3.64-3.56 (m, 4H),3.55-3.47 (m, 4H), 2.87-2.80 (m, 2H), 2.74 (dd, J=6.8, 12.8 Hz, 1H),2.49 (s, 3H), 2.47-2.40 (m, 1H), 2.36 (s, 6H), 1.42 (d, J=6.4 Hz, 3H),0.98-0.92 (m, 2H), 0.00 (s, 9H).

Step B: tert-butyl4-[2-[(1R)-2-(dimethylamino)-1-methyl-ethoxy]-7-[5-methyl-1-(2-trimethylsilylethoxymethyl)indazol-4-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate:To a solution of benzyl4-[2-[(1R)-2-(dimethylamino)-1-methyl-ethoxy]-7-[5-methyl-1-(2-trimethylsilylethoxymethyl)indazol-4-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(200 mg, 280 umol) and (Boc)₂₀ (122 mg, 559 umol, 129 uL) in MeOH (6.00mL) was added 10% Pd/C (80 mg) under N₂. The suspension was degassedunder vacuum and purged with H₂ several times. The mixture was stirredunder H₂ (15 psi) at 25° C. for 1 hour and 35° C. for 1 hour. Uponcompletion, the mixture was filtered and the filtrate concentrated undervacuum to give mixture of tert-butyl4-[2-[(1R)-2-(dimethylamino)-1-methyl-ethoxy]-7-[5-methyl-1-(2-trimethylsilylethoxymethyl)indazol-4-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylateand(2R)—N,N-dimethyl-2-[[7-[5-methyl-1-(2-trimethylsilylethoxymethyl)indazol-4-yl]-4-piperazin-1-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-2-yl]oxy]propan-1-amineas a mixture (110 mg). ES+APCI MS m/z 681.3 [M+H]⁺.

Step C:(2R)—N,N-dimethyl-2-[[7-(5-methyl-1H-indazol-4-yl)-4-piperazin-1-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-2-yl]oxy]propan-1-amine:(2R)—N,N-dimethyl-2-[[7-(5-methyl-1H-indazol-4-yl)-4-piperazin-1-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-2-yl]oxy]propan-1-amine(TFA) and[4-[2-[(1R)-2-(dimethylamino)-1-methyl-ethoxy]-4-piperazin-1-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl]-5-methyl-indazol-1-yl]methanol.A solution of 110 mg mixture of tert-butyl4-[2-[(1R)-2-(dimethylamino)-1-methyl-ethoxy]-7-[5-methyl-1-(2-trimethylsilylethoxymethyl)indazol-4-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylateand(2R)—N,N-dimethyl-2-[[7-[5-methyl-1-(2-trimethylsilylethoxymethyl)indazol-4-yl]-4-piperazin-1-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-2-yl]oxy]propan-1-aminein TFA (3.08 g, 27.0 mmol) was stirred at 30° C. for 1 hour. Uponcompletion, the mixture was concentrated under vacuum to give 260 mgmixture of(2R)—N,N-dimethyl-2-[[7-(5-methyl-1H-indazol-4-yl)-4-piperazin-1-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-2-yl]oxy]propan-1-amineand[4-[2-[(1R)-2-(dimethylamino)-1-methyl-ethoxy]-4-piperazin-1-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl]-5-methyl-indazol-1-yl]methanol.ES+APCI MS m/z 451.3 [M+H]⁺.

Step D:1-[4-[2-[(1R)-2-(dimethylamino)-1-methyl-ethoxy]-7-(5-methyl-1H-indazol-4-yl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one:To a solution of 260 mg mixture of(2R)—N,N-dimethyl-2-[[7-(5-methyl-1H-indazol-4-yl)-4-piperazin-1-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-2-yl]oxy]propan-1-amineand[4-[2-[(1R)-2-(dimethylamino)-1-methyl-ethoxy]-4-piperazin-1-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl]-5-methyl-indazol-1-yl]methanolin DCM (1.00 mL) cooled to −50° C. was added DIEA (594 mg, 4.59 mmol)followed by prop-2-enoyl prop-2-enoate (18.0 mg, 143 umol) dropwise andthe mixture was stirred at between −50° C. to −40° C. for 30 minutes.Upon completion, the mixture was concentrated under vacuum to give 100mg mixture of1-[4-[2-[(1R)-2-(dimethylamino)-1-methyl-ethoxy]-7-(5-methyl-1H-indazol-4-yl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-oneand1-[4-[2-[(1R)-2-(dimethylamino)-1-methyl-ethoxy]-7-[1-(hydroxymethyl)-5-methyl-indazol-4-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one.ES+APCI MS m/z 505.4 [M+H]⁺.

Step E:1-[4-[2-[(1R)-2-(dimethylamino)-1-methyl-ethoxy]-7-(5-methyl-1H-indazol-4-yl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one:A mixture of 100 mg of1-[4-[2-[(1R)-2-(dimethylamino)-1-methyl-ethoxy]-7-(5-methyl-1H-indazol-4-yl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-oneand1-[4-[2-[(1R)-2-(dimethylamino)-1-methyl-ethoxy]-7-[1-(hydroxymethyl)-5-methyl-indazol-4-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-onein THE (22 mL) and water (550 uL) was added NaOH (44.8 mg, 1.12 mmol)and the mixture stirred at 10° C. for 3 hours. Upon completion, themixture was concentrated under vacuum. The residue was diluted withwater (1 mL) and extracted with DCM (3×5 mL). The combined organics weredried over Na₂SO₄ and concentrated under vacuum. The residue waspurified by prep-HPLC (column: Phenomenex Synergi C18 150*25*10 um;mobile phase: [water (0.225% Formic Acid)-ACN]; B %: 10%-40%, 12 min) togive1-[4-[2-[(1R)-2-(dimethylamino)-1-methyl-ethoxy]-7-(5-methyl-1H-indazol-4-yl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one(16.2 mg, 29.2 umol, 99.0% purity, Formic Acid Salt) as a off-whitesolid. ES+APCI MS m/z 505.2 [M+H]⁺.

Example 1631-(4-(2-(2-(diethylamino)ethoxy)-7-(5-methyl-1H-indazol-4-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Step A: benzyl4-[2-[2-(diethylamino)ethoxy]-7-[5-methyl-1-(2-trimethylsilylethoxymethyl)indazol-4-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate:To a mixture of benzyl4-[2-methylsulfinyl-7-[5-methyl-1-(2-trimethylsilylethoxymethyl)indazol-4-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(500 mg, 739 umol) and 2-(diethylamino)ethanol (173 mg, 1.48 mmol, 197uL) in THE (10 mL) was added t-BuONa (213 mg, 2.22 mmol), and themixture stirred at 20° C. for 1 hour under N₂ atmosphere. The mixturewas cooled to 0° C. and HCl (2 M) was added until pH-7. The mixture wasfiltered and the filtrate was concentrated in vacuo. The residue waspurified by column chromatography using 0→10% MeOH/DCM as eluent to giveimpure material which was further purified by reversed phasechromatography to give benzyl4-[2-[2-(diethylamino)ethoxy]-7-[5-methyl-1-(2-trimethylsilylethoxymethyl)indazol-4-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(220 mg, 295 umol, 39.9% yield). ES+APCI MS m/z 729.3 [M+H]⁺.

Step B:N,N-diethyl-2-[[7-[5-methyl-1-(2-trimethylsilylethoxymethyl)indazol-4-yl]-4-piperazin-1-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-2-yl]oxy]ethanamine:To a solution of benzyl4-[2-[2-(diethylamino)ethoxy]-7-[5-methyl-1-(2-trimethylsilylethoxymethyl)indazol-4-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(120 mg, 164 umol) in MeOH (10 mL) was added Pd(OH)₂ (99.4 mg, 10%purity) and HCl/MeOH (4 M, 823.05 uL) under N₂. The suspension wasdegassed under vacuum and purged with H₂ several times. The mixture wasstirred under H₂ (15 psi) at 25° C. for 1 hour. The mixture wasconcentrated in vacuo to giveN,N-diethyl-2-[[7-[5-methyl-1-(2-trimethylsilylethoxymethyl)indazol-4-yl]-4-piperazin-1-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-2-yl]oxy]ethanamine(105 mg, 157.24 umol). ES+APCI MS m/z 595.4 [M+H]⁺.

Step C:1-[4-[2-[2-(diethylamino)ethoxy]-7-[5-methyl-1-(2-trimethylsilylethoxymethyl)indazol-4-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one:To a mixture of N,N-diethyl-2-[[7-[5-methyl-1-(2-trimethylsilylethoxymethyl)indazol-4-yl]-4-piperazin-1-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-2-yl]oxy]ethanamine(105 mg, 158 umol, 2 HCl) and DIEA (204 mg, 1.58 mmol, 276 uL) in DCM (8mL) at −40° C. was added a solution of prop-2-enoyl prop-2-enoate (15.9mg, 126.4 umol) in DCM (2 mL) under nitrogen atmosphere and the reactionstirred for 1 hour. The reaction mixture was quenched by addition NaHCO₃(500 uL) at −40° C., and then diluted with water (10 mL). The aqueouslayer was extracted with DCM (10 ml), dried over Na₂SO₄, filtered andconcentrated under reduced pressure. The residue was purified by columnchromatography using 0-20% MeOH/DCM as eluent to give1-[4-[2-[2-(diethylamino)ethoxy]-7-[5-methyl-1-(2-trimethylsilylethoxymethyl)indazol-4-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one(60.0 mg, 71.2 umol, 45.0% yield). ES+APCI MS m/z 649.3 [M+H]⁺.

Step D:1-[4-[2-[2-(diethylamino)ethoxy]-7-(5-methyl-1H-indazol-4-yl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one:To a solution of1-[4-[2-[2-(diethylamino)ethoxy]-7-[5-methyl-1-(2-trimethylsilylethoxymethyl)indazol-4-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one(50 mg, 77.0 umol) in DCM (500 uL) was added TFA (175 mg, 1.54 mmol, 114uL). The mixture was stirred at 15° C. for 16 hours. The reactionmixture was concentrated under vacuum and the residue purified byprep-HPLC (column: Phenomenex Gemini C18 250*50 mm*10 um; mobile phase:[water (0.05% ammonia hydroxide v/v)-ACN]; B %: 32%-62%, 12 min) to give1-[4-[2-[2-(diethylamino)ethoxy]-7-(5-methyl-1H-indazol-4-yl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one(16.0 mg, 30.2 umol, 39.2% yield). ES+APCI MS m/z 519.3 [M+H]⁺.

Example 1641-(4-(7-(5-methyl-1H-indazol-4-yl)-2-(2-(piperidin-1-yl)ethoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)ethanone

Step A: benzyl 4-[7-[5-methyl-1-(2-trimethylsilylethoxymethyl)indazol-4-yl]-2-[2-(1-piperidyl)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate

To a solution of benzyl4-[2-methylsulfinyl-7-[5-methyl-1-(2-trimethylsilylethoxymethyl)indazol-4-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(500 mg, 739 umol) and 2-(1-piperidyl)ethanol (191 mg, 1.48 mmol, 197uL) in toluene (20 mL) was added t-BuONa (213 mg, 2.22 mmol). Themixture was stirred at 20° C. for 1 hour under N₂ atmosphere. Themixture was cooled to 0° C. and HCl (2 M) was added until pH-7. Themixture was filtered and the filtrate concentrated in vacuo. The residuewas purified by column chromatography using 0→10% MeOH/DCM as eluent togive benzyl 4-[7-[5-methyl-1-(2-trimethylsilylethoxymethyl)indazol-4-yl]-2-[2-(1-piperidyl)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(300 mg, 404 umol, 54.7% yield). ES+APCI MS m/z 741.4 [M+H]⁺.

Step B:7-(5-methyl-1H-indazol-4-yl)-4-piperazin-1-yl-2-[2-(1-piperidyl)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine

A solution of benzyl 4-[7-[5-methyl-1-(2-trimethylsilylethoxymethyl)indazol-4-yl]-2-[2-(1-piperidyl)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(250 mg, 337 umol) in TFA (10 mL) was stirred at 80° C. for 1 hour. Thereaction mixture was concentrated under vacuum to give7-(5-methyl-1H-indazol-4-yl)-4-piperazin-1-yl-2-[2-(1-piperidyl)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine(200 mg, 283 umol, 84.1% yield). ES+APCI MS m/z 477.3 [M+H]⁺.

Step C:1-[4-[7-(5-methyl-1H-indazol-4-yl)-2-[2-(1-piperidyl)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one

To a mixture of7-(5-methyl-1H-indazol-4-yl)-4-piperazin-1-yl-2-[2-(1-piperidyl)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine(200 mg, 283 umol, 2TFA) and DIEA (366 mg, 2.84 mmol, 495 uL) in DCM (8mL) at −40° C. was added a solution of prop-2-enoyl prop-2-enoate (28.6mg, 227 umol) DCM (2 mL) under nitrogen atmosphere and the reactionstirred for 1 hour. The reaction mixture was quenched by addition NaHCO₃(500 uL) at −40° C., and then diluted with water (10 mL) and DCM (10ml). The separated organic layer was dried over Na₂SO₄, filtered andconcentrated under reduced pressure. The residue was purified byprep-HPLC (column: Phenomenex Gemini C18 250*50 mm*10 um; mobile phase:[water (0.05% ammonia hydroxide v/v)-ACN]; B %: 30%-60%, 12 min).1-[4-[7-(5-methyl-1H-indazol-4-yl)-2-[2-(1-piperidyl)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one(6.00 mg, 11.1 umol, 3.94% yield, 99.0% purity). ES+APCI MS m/z 531.4[M+H]⁺.

Example 1651-[4-[7-(2-fluoro-3-hydroxy-1-naphthyl)-2-(3-morpholinopropoxy)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one

Step A: 3-methoxynaphthalen-1-ol

To a solution of naphthalene-1,3-diol (20 g, 125 mmol) in MeOH (150 mL)was added HCl/MeOH (4 M, 250 mL) at 0° C. The mixture was warmed up to18° C. and stirred for 36 hours. The mixture was concentrated undervacuum. The residue was purified by column chromatography over silicagel (petroleum ether/ethyl acetate 100/1 to 1/1). The desired fractionswere collected and concentrated under vacuum to give3-methoxynaphthalen-1-ol (11 g, 62.5 mmol, 50.1% yield, 99% purity) as alight yellow solid. ES+APCI MS m/z 175.1 [M+H]⁺.

Step B: 4-bromo-3-methoxy-naphthalen-1-ol

To a solution of 3-methoxynaphthalen-1-ol (0.50 g, 2.87 mmol) in THF (10mL) was added a solution of NBS (562 mg, 3.16 mmol) in THF (3.00 mL) at0° C. After stirring at 0° C. for 2 hours, the mixture was concentratedunder vacuum, diluted with H₂O (5 mL), extracted with dichloromethane(3×10 mL). The combined extracts were washed with saturated sodiumchloride (1×20 mL), dried over Na₂SO₄, filtered and concentrated undervacuum. The residue was purified by column chromatography (SiO₂,petroleum ether/ether acetate=3/1) to give4-bromo-3-methoxy-naphthalen-1-ol (0.43 g, 1.43 mmol, 49.7% yield) as ayellow solid. ES+APCI MS m/z 253 [M+H]⁺.

Step C: 4-bromo-2-fluoro-3-methoxy-naphthalen-1-ol

To a solution of 4-bromo-3-methoxy-naphthalen-1-ol (4.00 g, 15.8 mmol)in acetonitrile (20 mL) was added a solution of1-(chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane;ditetrafluoroborate (6.72 g, 19.0 mmol) in acetonitrile (20 mL) at −40°C. After stirring at −40° C. for 1 hour and 10° C. for 3 hours, themixture was concentrated under vacuum. The residue was purified bycolumn chromatography (SiO₂, petroleum ether/ether acetate=3/1) to give4-bromo-2-fluoro-3-methoxy-naphthalen-1-ol (4.00 g, 10.6 mmol, 67.2%yield) as a yellow solid. ES+APCI MS m/z 271.0 [M+H]⁺.

Step D: 2-fluoro-3-methoxy-naphthalen-1-ol

A mixture of 4-bromo-2-fluoro-3-methoxy-naphthalen-1-ol (2.00 g, 7.38mmol) and 10% Pd/C (0.01 g) in ethyl acetate (20 mL) was stirred at 10°C. for 1 hour under H₂ at 15 psi. The mixture was filtered andconcentrated under vacuum to give 2-fluoro-3-methoxy-naphthalen-1-ol(1.60 g, crude) as yellow oil and used into next step without furtherpurification. ES+APCI MS m/z 193.0 [M+H]⁺.

Step E: (2-fluoro-3-methoxy-1

naphthyl) trifluoromethanesulfonate: To a solution of2-fluoro-3-methoxy-naphthalen-1-ol (1.60 g, crude) and TEA (1.85 g, 18.3mmol, 2.55 mL) in dichloromethane (30 mL) was addedtrifluoromethylsulfonyl trifluoromethanesulfonate (2.35 g, 8.33 mmol,1.37 mL) at −78° C. for 1 hour. The mixture was quenched with saturatedammonium chloride (30 mL), extracted with ethyl acetate (3×20 mL),washed with saturated sodium chloride (1×50 mL), dried over Na₂SO₄,filtered and concentrated under vacuum. The residue was purified bycolumn chromatography (SiO₂, petroleum ether/ether acetate=3/1) to give(2-fluoro-3-methoxy-1-naphthyl) trifluoromethanesulfonate (1.10 g, 2.07mmol, two steps 24.9% yield) as a yellow solid. ES+APCI MS m/z 324.9[M+H]⁺.

Step F: tert-butyl4-[7-(2-fluoro-3-methoxy-1-naphthyl)-2-(3-morpholinopropoxy)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate

A mixture of tert-butyl4-[2-(3-morpholinopropoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(0.40 g, 865 umol), (2-fluoro-3-methoxy-1-naphthyl)trifluoromethanesulfonate (561 mg, 1.73 mmol), RuPhos (80.7 mg, 173umol), Pd₂(dba)₃ (79.2 mg, 86.5 umol) and t-BuONa (249 mg, 2.59 mmol) intoluene (10 mL) was stirred at 110° C. for 5 hours under N₂. The mixturewas diluted with water (10 mL), extracted with ether acetate (3×10 mL).The extracts were washed with saturated sodium chloride (1×20 mL), driedover Na₂SO₄, filtered and concentrated under vacuum. The residue waspurified by reversed phase flash chromatography [water (0.1% FormicAcid)/acetonitrile] to give tert-butyl4-[7-(2-fluoro-3-methoxy-1-naphthyl)-2-(3-morpholinopropoxy)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(0.35 g, 495 umol, 57.2% yield) as a yellow oil. ES+APCI MS m/z 637.1[M+H]⁺.

Step G:4-[3-[[7-(2-fluoro-3-methoxy-1-naphthyl)-4-piperazin-1-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-2-yl]oxy]propyl]morpholine

A mixture of tert-butyl4-[7-(2-fluoro-3-methoxy-1-naphthyl)-2-(3-morpholinopropoxy)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(0.40 g, 628. umol) and TFA (1.07 g, 9.42 mmol, 698 uL) indichloromethane (0.70 mL) was stirred at 10° C. for 1 hour. The mixturewas concentrated under vacuum to give4-[3-[[7-(2-fluoro-3-methoxy-1-naphthyl)-4-piperazin-1-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-2-yl]oxy]propyl]morpholine(0.41 g, crude, TFA) as a yellow oil and used into next step withoutfurther purification. ES+APCI MS m/z 537.5 [M+H]⁺.

Step H:1-[4-[7-(2-fluoro-3-methoxy-1-naphthyl)-2-(3-morpholinopropoxy)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one

To a solution of4-[3-[[7-(2-fluoro-3-methoxy-1-naphthyl)-4-piperazin-1-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-2-yl]oxy]propyl]morpholine(0.41 g, crude, TFA salt) and TEA (635 mg, 6.27 mmol, 873 uL) indichloromethane (5.0 mL) was added prop-2-enoyl prop-2-enoate (79.1 mg,627 umol) at −40° C. After stirring at −40° C. for 0.5 h, the mixturewas quenched with methanol (0.10 mL) and concentrated under vacuum. Theresidue was purified by column chromatography (Al₂O₃,dichloromethane/methanol=10/1) to give1-[4-[7-(2-fluoro-3-methoxy-1-naphthyl)-2-(3-morpholinopropoxy)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one(0.25 g, 411 umol, two steps 65.5% yield) as a yellow oil. ES+APCI MSm/z 591.0 [M+H]⁺.

Step I:1-[4-[7-(2-fluoro-3-hydroxy-1-naphthyl)-2-(3-morpholinopropoxy)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one:

To a solution of1-[4-[7-(2-fluoro-3-methoxy-1-naphthyl)-2-(3-morpholinopropoxy)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one(0.20 g, 339 umol) in dichloromethane (4.00 mL) was added BBr₃ (424 mg,1.69 mmol, 163 uL) at −78° C. for 0.5 hour and stirred at 0° C. for 2hours. The mixture was quenched with saturated sodium bicarbonate (5 mL)at −78° C. and stirred at 0° C. for 0.5 h. The mixture was extractedwith dichloromethane (3×10 mL) and concentrated under vacuum. Theresidue was purified by prep-HPLC (column: Phenomenex Synergi C18150*25*10 um; mobile phase: [water (0.225% Formic Acid)-ACN]; B %:13%-45%, 7 min) to give1-[4-[7-(2-fluoro-3-hydroxy-1-naphthyl)-2-(3-morpholinopropoxy)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one(35.2 mg, 60.8 umol, 17.9% yield, 99.4% purity) as a yellow solid.ES+APCI MS m/z 577.0[M+H]⁺.

Example 1661-[4-[7-(6-hydroxy-2-methyl-1,3-benzothiazol-4-yl)-2-(3-morpholinopropoxy)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one

Step A: 4-triisopropylsilyloxyaniline

To a solution of 4-aminophenol (5.00 g, 45.8 mmol, 7.14 mL) in DCM (50.0mL) was added imidazole (4.06 g, 59.6 mmol). TIPSCI (13.3 g, 68.7 mmol,14.7 mL) was added to the mixture dropwise. The mixture was stirred at15° C. for 12 hours. Upon completion, the reaction mixture was filteredand the filtrate was concentrated under vacuum. The residue was purifiedby automated flash chromatography system (PE/EA 100/1 to 3/1) to give4-triisopropylsilyloxyaniline (9.46 g, 33.9 mmol, 73.9% yield, 95.0%purity) as a black oil.

¹H NMR (400 MHz, chloroform-d) 6=6.74-6.71 (m, 1H), 6.71-6.69 (m, 1H),6.60-6.58 (m, 1H), 6.58-6.55 (m, 1H), 3.66-2.98 (m, 2H), 1.28-1.16 (m,3H), 1.11-1.06 (m, 18H)

Step B: 2,6-dibromo-4-triisopropylsilvloxy-aniline

To a solution of 4-triisopropylsilyloxyaniline (7.30 g, 27.5 mmol) inDCM (73.0 mL) and MeOH (73.0 mL) was added Br₂ (11.0 g, 68.8 mmol, 3.55mL) in DCM (5 mL) dropwise at 0° C. The mixture was stirred at 15° C.for 5 hours. Upon completion, the mixture was diluted with sodiumsulfite solution (60 mL) and extracted with DCM (3×200 mL). The organiclayers were dried over Na₂SO₄ and concentrated under vacuum. The residuewas purified by column chromatography (PE/EA 50/1 to 1/1) to give2,6-dibromo-4-triisopropylsilyloxy-aniline (10.8 g, 23.2 mmol, 84.4%yield, 90.8% purity) as a brown oil. ES+APCI MS m/z 423.9[M+H]⁺.

Step C: N-(2,6-dibromo-4-triisopropylsilyloxy-phenyl)acetamide

To a solution of 2,6-dibromo-4-triisopropylsilyloxy-aniline (10.4 g,24.6 mmol) and CH₃COOH (52 mL) was added acetic anhydride (10.9 g, 107mmol, 10 mL). The reaction mixture was stirred at 90° C. for 1 hour.Upon completion, water (100 mL) and DCM (200 mL) were added and layerswere separated. The aqueous phase was extracted with DCM (100 mL×2). Thecombined extracts were washed with 5% Na₂CO₃ (80 mL), washed with brine(100 mL), dried over Na₂SO₄ and concentrated under vacuum. The residuewas purified by column chromatography (PE/EA 50/1 to 1:1) to giveN-(2,6-dibromo-4-triisopropylsilyloxy-phenyl)acetamide (7.32 g, 14.2mmol, 57.6% yield, 90.0% purity) as a brown solid.

¹H NMR (400 MHz, chloroform-d) 6=7.16 (s, 1H), 7.11 (s, 2H), 2.21 (s,3H), 1.28-1.24 (m, 3H), 1.12-1.09 (m, 18H).

Step D: N-(2,6-dibromo-4-triisopropylsilyloxy-phenyl)thioacetamide

To a solution of N-(2,6-dibromo-4-triisopropylsilyloxy-phenyl)acetamide(7.22 g, 15.5 mmol) in toluene (116 mL) was added LAWESSON'S REAGENT(3.14 g, 7.76 mmol). The mixture was heated to 110° C. for 2 hours. Uponcompletion, the mixture was concentrated under vacuum. The residue waspurified by column chromatography (PE/EA 100/1 to 1/1)N-(2,6-dibromo-4-triisopropylsilyloxy-phenyl)thioacetamide (5.41 g, 8.40mmol, 54.1% yield, 74.7% purity) as a yellow oil. ES+APCI MS m/z481.9[M+H]⁺.

Step E: 4-bromo-2-methyl-1,3-benzothiazol-6-ol

CuI (94.2 mg, 494 umol) was added to a solution ofN-(2,6-dibromo-4-triisopropylsilyloxy-phenyl)thioacetamide (2.38 g, 4.94mmol), 1,10-phenanthroline (134 mg, 741 umol) and Cs₂CO₃ (4.83 g, 14.8mmol) in DME (48.0 mL). Then the reaction mixture was stirred at 80° C.for 12 hours under N₂. Upon completion, the reaction mixture wasfiltered and the filtrate was concentrated. The residue was purified bycolumn chromatography (PE/EA 50/1 to 0/1) to give4-bromo-2-methyl-1,3-benzothiazol-6-ol (1.33 g, 3.54 mmol, 71.7% yield,65.0% purity) as a brown oil.

¹H NMR (400 MHz, DMSO-d₆) δ=7.33 (d, J=2.4 Hz, 1H), 7.14 (d, J=2.4 Hz,1H), 3.40-3.33 (m, 1H), 2.72 (s, 3H).

Step F: 6-benzyloxy-4-bromo-2-methyl-1,3-benzothiazole

To a mixture of 4-bromo-2-methyl-1,3-benzothiazol-6-ol (1.28 g, 5.24mmol) and K₂CO₃ (2.17 g, 15.72 mmol) in ACN (26.0 mL) was added BnBr(988 mg, 5.76 mmol, 685 uL). The reaction mixture was stirred at 45° C.for 1 hour. Upon completion, the reaction mixture was filtered and thefiltrate was concentrated. The residue was purified by columnchromatography (PE/EA 200/1 to 10/1) to give6-benzyloxy-4-bromo-2-methyl-1,3-benzothiazole (1.10 g, 3.13 mmol, 59.7%yield, 95.0% purity) as a light yellow solid. ES+APCI MS m/z 336.2[M+H]⁺.

Step G: benzyl4-[7-(6-benzyloxy-2-methyl-1,3-benzothiazol-4-yl)-2-(3-morpholinopropoxy)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate

Benzyl4-[2-(3-morpholinopropoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(400 mg, 805 umol), 6-benzyloxy-4-bromo-2-methyl-1,3-benzothiazole (323mg, 967 umol), RuPhos (75.2 mg, 161 umol), Cs₂CO₃ (787 mg, 2.42 mmol)and Pd₂(dba)₃ (73.8 mg, 80.6 umol) in toluene (16 mL) was stirring at85° C. for 16 hours under N₂. Upon completion, the reaction mixture wasfiltered and the filtrate was concentrated. The residue was purified bycolumn chromatography over Al₂O₃(PE/EA 10/1 to 0/1) to give benzyl4-[7-(6-benzyloxy-2-methyl-1,3-benzothiazol-4-yl)-2-(3-morpholinopropoxy)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(340 mg, 408 umol, 50.7% yield, 90.0% purity) as a yellow oil. ES+APCIMS m/z 750.5[M+H]⁺.

Step H:2-methyl-4-[2-(3-morpholinopropox)-4-piperazin-1-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl]-1,3-benzothiazol-6-ol

To a solution of benzyl4-[7-(6-benzyloxy-2-methyl-1,3-benzothiazol-4-yl)-2-(3-morpholinopropoxy)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(160 mg, 213 umol) in MeOH (4 mL) was added HCl/MeOH (4 M, 533 uL),followed by Pd(OH)₂/C (80 mg, 533 umol) under N₂. The suspension wasdegassed under vacuum and purged with H₂ several times. The mixture wasstirred under H₂ (15 psi) at 40° C. for 8 hours. Upon completion, thereaction mixture was filtered and the filtrate was concentrated to give2-methyl-4-[2-(3-morpholinopropoxy)-4-piperazin-1-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl]-1,3-benzothiazol-6-ol(110 mg, 126 umol, 59.2% yield, 68.7% purity, 2 HCl) as a yellow solidwhich was used directly in the next step without further purification.ES+APCI MS m/z 526.2[M+H]⁺.

Step I:1-[4-[7-(6-hydroxy-2-methyl-1,3-benzothiazol-4-yl)-2-(3-morpholinopropoxy)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one

To a solution of2-methyl-4-[2-(3-morpholinopropoxy)-4-piperazin-1-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl]-1,3-benzothiazol-6-ol(110 mg, 184 umol, 2 HCl) and DIEA (143 mg, 1.10 mmol, 193 uL) in DCM(2.00 mL) was added prop-2-enoyl prop-2-enoate (18.5 mg, 147 umol)dropwise at −50° C. The mixture was stirred at −40-−20° C. for 30minutes. Upon completion, the mixture was quenched by MeOH (0.5 mL) andconcentrated under vacuum. The residue was diluted with water (2 mL) andextracted with DCM (3×6 mL). The organic layers were dried over Na₂SO₄and concentrated under vacuum. The residue was purified by columnchromatography over Al₂O₃(DCM/MeOH 20/1 to 10/1), prep-HPLC (column:Gemini 150*25 5u; mobile phase: [water (0.05% ammonia hydroxidev/v)-ACN]; B %: 21%-51%, 12 min) to give1-[4-[7-(6-hydroxy-2-methyl-1,3-benzothiazol-4-yl)-2-(3-morpholinopropoxy)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one(32.4 mg, 55.4 umol, 30.2% yield, 99.1% purity) as a yellow solid.ES+APCI MS m/z 580.4[M+H]⁺.

Example 1671-(4-(7-(5-hydroxy-2-methyl-1H-indol-7-yl)-2-(3-morpholinopropoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Step A: 2-bromo-4-methoxyaniline

At −10° C., to a solution of 4-methoxyaniline (100 g, 812 mmol) in THE(3 L) was added N-bromosuccinimide (152 g, 853 mmol) in three portionsand the mixture was stirred at the same temperature for 30 min. Themixture was concentrated under reduced pressure. The residue waspurified by column chromatography. (petroleum ether/ethyl acetate 15/1)to give 2-bromo-4-methoxyaniline as red oil (30.58 g, 18.6% yield). 1HNMR (400 MHz, CDCl₃) δ=7.01 (d, J=2.4 Hz, 1H), 6.74-6.70 (m, 2H),3.85-3.74 (m, 2H), 3.73 (s, 3H).

Step B: 1-(2-amino-3-bromo-5-methoxyphenyl)-2-chloropropan-1-one

To a 0° C. solution of 2-bromo-4-methoxy-aniline (15.0 g, 74.2 mmol) in1,1-dichloroethane (220 mL) was added boron trichloride (1.00 M, 89.1mL), 2-chloropropanenitrile (9.97 g, 111 mmol) and titaniumtetrachloride (16.9 g, 89.1 mmol). The mixture was heated at 85° C. for24 hours. The mixture was poured into ice and hydrochloric acid (20%,300 mL) at 0° C., concentrated and the residue was refluxed for 0.5hour. This mixture was basified at 0° C. with sodium hydroxide(saturated aqueous, 120 mL) until pH 4 was attained and then extractedwith ethyl acetate (300 mL×2). The combined organic extracts were washedwith brine (200 mL), dried with anhydrous sodium sulfate andconcentrated under reduced pressure. The residue was purified by columnchromatography (petroleum ether/ethyl acetate/dichloromethane 50/1/1),to give 1-(2-amino-3-bromo-5-methoxyphenyl)-2-chloropropan-1-one asyellow solid (18.7 g, 86.3% yield). ¹H NMR (400 MHz, CDCl₃) δ=7.37 (d,J=2.8 Hz, 1H), 7.32 (d, J=2.8 Hz, 1H), 6.60 (brs, 2H), 5.25 (q, J=6.4Hz, 1H), 3.80 (s, 3H), 1.74 (d, J=6.4 Hz, 3H).

Step C: 7-bromo-5-methoxy-2-methyl-1H-indole

To a solution of1-(2-amino-3-bromo-5-methoxy-phenyl)-2-chloro-propan-1-one (18.7 g, 64.1mmol) in dioxane (500 mL) and H₂O (50 mL) was added NaBH₄ (2.67 g, 70.5mmol) and this mixture stirred at 100° C. for 15 hours. The mixture wascooled, diluted with hydrochloric acid (aq., 0.10 M, 100 mL) andextracted with dichloromethane (300 mL×2). The organics were washed withbrine (200 mL), dried with anhydrous sodium sulfate and concentratedunder reduced pressure. The residue was purified by columnchromatography (petroleum ether/ethyl acetate 25/1) to give7-bromo-5-methoxy-2-methyl-1H-indole as yellow solid (7.01 g, 45.6%yield). ¹H NMR (400 MHz, CDCl₃) δ=7.91 (brs, 1H), 7.03-6.91 (m, 2H),6.23 (d, J=1.2 Hz, 1H), 3.84 (s, 3H), 2.46 (s, 3H).

Step D: tert-butyl4-(7-(5-methoxy-2-methyl-1H-indol-7-yl)-2-(3-morpholinopropoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate

To a mixture of tert-butyl4-[2-(3-morpholinopropoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(275 mg, 594 umol) and 7-bromo-5-methoxy-2-methyl-1H-indole (130 mg, 540umol) in 2-methyl-2-butanol (15.0 mL) was added ^(t)BuONa (104 mg, 1.08mmol) andchloro(2-dicyclohexylphosphino-2′,6‘-di-’-propoxy-1,1′-biphenyl)[2-(2-aminoethylphenyl)]palladium(II)methyl-t-butyl ether adduct (44.1 mg, 54.0 umol). This mixture stirredat 90° C. for 8 hours under a N₂ atmosphere. The mixture was filtered,concentrated under reduced pressure. The residue was purified byprep-TLC (dichloromethane/methanol 10/1), to give tert-butyl4-(7-(5-methoxy-2-methyl-1H-indol-7-yl)-2-(3-morpholinopropoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylateas yellow oil (131 mg, 36.8% yield). ES+APCI MS m/z 622.4[M+H]⁺.

Step E:4-[3-[[7-(5-methoxy-2-methyl-H-indol-7-yl)-4-piperazin-1-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-2-yl]oxy]propyl]morpholine

To a 0° C. solution of tert-butyl4-[7-(5-methoxy-2-methyl-1H-indol-7-yl)-2-(3-morpholinopropoxy)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(131 mg, 211 umol) in dichloromethane (10 mL) was added trifluoroaceticacid (2.00 mL) dropwise and the reaction stirred at 15° C. for 3 hours.The mixture was concentrated under reduced pressure, and the residue wasused in the next step without further purification. (126 mg crudeproduct). ES+APCI MS m/z 522.4[M+H]⁺.

Step F:1-(4-(7-(5-methoxy-2-methyl-1H-indol-7-yl)-2-(3-morpholinopropoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

To a −60° C. solution of4-[3-[[7-(5-methoxy-2-methyl-1H-indol-7-yl)-4-piperazin-1-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-2-yl]oxy]propyl]morpholine(74 mg, 116 umol, trifluoroacetic acid salt) in dichloromethane (5 mL)was added diisopropylethylamine (45.1 mg, 349 umol, 60.8 uL) and themixture stirred at the same temperature for 10 min. The mixture wasquenched with citric acid (aq., 1.00 mL), extracted with dichloromethane(10 mL×2), washed with brine (15 mL), dried over anhydrous sodiumsulfate and concentrated under vacuum. The residue was purified byprep-TLC to give1-(4-(7-(5-methoxy-2-methyl-1H-indol-7-yl)-2-(3-morpholinopropoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-oneas yellow solid (31 mg, 39.2% yield). ES+APCI MS m/z 576.4[M+H]⁺.

Step G:1-(4-(7-(5-hydroxy-2-methyl-1H-indol-7-yl)-2-(3-morpholinopropoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

To a −78° C. solution of1-[4-[7-(5-methoxy-2-methyl-1H-indol-7-yl)-2-(3-morpholinopropoxy)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one(26 mg, 45.2 umol) in dichloromethane (5 mL) was added boron tribromide(56.6 mg, 226 umol, 21.8 uL). The reaction was allowed to warm to 0° C.and stirred for 12 hours. The mixture was neutralized withy NaHCO₃ (aq.,3 mL) and extracted with dichloromethane (5 mL×2), washed with brine (10mL), dried by anhydrous sodium sulfate, concentrated under vacuum. Theresidue was purified by prep-HPLC to give1-(4-(7-(5-hydroxy-2-methyl-1H-indol-7-yl)-2-(3-morpholinopropoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-oneas yellow solid (8.16 mg, 29.1% yield, 90.3% purity). ES+APCI MS m/z562.5[M+H]⁺.

Example 1681-(3-(hydroxymethyl)-4-(7-(3-hydroxynaphthalen-1-yl)-2-(3-morpholinopropoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Step A: Tert-butyl3-[[tert-butyl(diphenyl)silyl]oxymethyl]piperazine-1-carboxylate

To a solution of tert-butyl 3-(hydroxymethyl)piperazine-1-carboxylate(3.50 g, 16.2 mmol) in THE (30 mL) was added NaH (3.24 g, 80.9 mmol,60.0% purity) at 0° C. After stirring for 30 minutes, TBDPSCI (6.67 g,24.3 mmol, 6.23 mL) was added in one portion. The mixture was warmed to10° C. and stirred for 12 hours under N₂ atmosphere. The reactionmixture was quenched by addition water at 0° C., and then extracted withDCM (200 mL). The organic layer was dried with Na₂SO₄, filtered andconcentrated under reduced pressure. The residue was purified by columnchromatography (SiO₂, Petroleum ether/Ethyl acetate 1/0 to 1/2) to givetert-butyl3-[[tert-butyl(diphenyl)silyl]oxymethyl]piperazine-1-carboxylate (6.34g, 12.1 mmol, 74.8% yield, 86.8% purity) as a colorless oil. ES+APCI MSm/z455.3[M+H]⁺.

Step B:tert-butyl4-(7-benzyl-2-chloro-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl)-3-[[tert-butyl(diphenyl)silyl]oxymethyl]piperazine-1-carboxylate

A mixture of tert-butyl 3-[[tert-butyl(diphenyl)silyl]oxymethyl]piperazine-1-carboxylate (7.25 g, 13.9 mmol),7-benzyl-2,4-dichloro-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine (3.89 g,13.2 mmol) and DIEA (4.27 g, 33.0 mmol, 5.77 mL) in DMSO (60 mL) wasstirred at 55° C. for 24 hours under N₂ atmosphere. The reaction mixturewas diluted with ethyl acetate (300 mL) and washed with brine (3×150mL). The organic layer was dried over Na₂SO₄, filtered and concentratedunder reduced pressure. The residue was purified by columnchromatography (SiO₂, Petroleum ether/Ethyl acetate 1/0 to 3/1) to givetert-butyl4-(7-benzyl-2-chloro-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl)-3-[[tert-butyl(diphenyl)silyl]oxymethyl]piperazine-1-carboxylate(4.50 g, 5.91 mmol, 44.7% yield, 93.5% purity) as a yellow solid.ES+APCI MS m/z 721.3[M+H]⁺.

Step C:tert-butyl4-[7-benzyl-2-(3-morpholinopropoxy)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-3-[[tert-butyl(diphenyl)silyl]oxymethyl]piperazine-1-carboxylate

A mixture of tert-butyl 4-(7-benzyl-2-chloro-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl)-3-[[tert-butyl(diphenyl)silyl]oxymethyl]piperazine-1-carboxylate(2.00 g, 2.81 mmol), 3-morpholinopropan-1-ol (815 mg, 5.62 mmol),Pd(OAc)₂ (94.6 mg, 422 umol), BINAP (350 mg, 562 umol) and t-BuONa (674mg, 7.03 mmol) in toluene (30 mL) was degassed and purged with N₂ for 3times, and then the mixture was heated to 110° C. and stirred for 3hours under N₂ atmosphere. After completion, the reaction mixture wasfiltered and concentrated under reduced pressure. The residue waspurified by column chromatography (SiO₂, DCM/MeOH 70/1 to 20/1) to givetert-butyl4-[7-benzyl-2-(3-morpholinopropoxy)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-3-[[tert-butyl(diphenyl)silyl]oxymethyl]piperazine-1-carboxylate(1.50 g, 1.69 mmol, 60.0% yield, 92.3% purity) as a yellow solid.ES+APCI MS m/z 821.4[M+H]⁺.

Step D: tert-butyl3-[[tert-butyl(diphenyl)silyl]oxymethyl]-4-[2-(3-morpholinopropoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate

To a solution of tert-butyl4-[7-benzyl-2-(3-morpholinopropoxy)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-3-[[tert-butyl(diphenyl)silyl]oxymethyl]piperazine-1-carboxylate(1.50 g, 1.83 mmol) in MeOH (20 mL) was added Pd—C (10%, 1.5 g) underN₂. The suspension was degassed under vacuum and purged with H₂ severaltimes. The mixture was stirred under H₂ (50 psi) at 50° C. for 24 hours.The reaction mixture was filtered and concentrated under reducedpressure to give tert-butyl3-[[tert-butyl(diphenyl)silyl]oxymethyl]-4-[2-(3-morpholinopropoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(988 mg, 1.21 mmol, 66.1% yield, 89.5% purity) as a colorless oil, whichwas used directly for next step without further purification. ES+APCI MSm/z 731.5[M+H]⁺.

Step E:tert-butyl4-[7-(3-benzyloxy-1-naphthyl)-2-(3-morpholinopropoxy)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-3-[[tert-butyl(diphenyl)silyl]oxymethyl]piperazine-1-carboxylate

A mixture of tert-butyl3-[[tert-butyl(diphenyl)silyl]oxymethyl]-4-[2-(3-morpholinopropoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(731 mg, 1.00 mmol), 3-benzyloxy-1-bromo-naphthalene (783 mg, 2.50mmol), [2-(2-aminophenyl)phenyl]palladium(1+);dicyclohexyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphane;methanesulfonate (169 mg, 200 umol), Cs₂CO₃ (815 mg, 2.50 mmol) intoluene (15 mL) was degassed and purged with N₂ 3 times, and then themixture was stirred at 60° C. for 24 hours under N₂ atmosphere. Thereaction mixture was filtered and concentrated under reduced pressure todryness and purified by column chromatography (SiO₂, DCM/MeOH=70/1 to30/1) to givetert-butyl4-[7-(3-benzyloxy-1-naphthyl)-2-(3-morpholinopropoxy)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-3-[[tert-butyl(diphenyl)silyl]oxymethyl]piperazine-1-carboxylate(250 mg, 188 umol, 18.8% yield, 72.3% purity) as a yellow solid. ES+APCIMS m/z 963.4[M+H]⁺.

Step F: tert-butyl3-[[tert-butyl(diphenyl)silyl]oxymethyl]-4-[7-(3-hydroxy-1-naphthyl)-2-(3-morpholinopropoxy)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate

To a solution of tert-butyl4-[7-(3-benzyloxy-1-naphthyl)-2-(3-morpholinopropoxy)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-3-[[tert-butyl(diphenyl)silyl]oxymethyl]piperazine-1-carboxylate(250 mg, 188 umol) in MeOH (3 mL) was added 10% Pd/C (0.25 g) under N₂.The suspension was degassed under vacuum and purged with H₂ severaltimes. The mixture was stirred under H₂ (15 psi) at 50° C. for 3 hours.After completion, the reaction mixture was filtered and concentratedunder reduced pressure to dryness to give tert-butyl3-[[tert-butyl(diphenyl)silyl]oxymethyl]-4-[7-(3-hydroxy-1-naphthyl)-2-(3-morpholinopropoxy)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(180 mg, 128 umol, 68.1% yield, 62.0% purity) as a dark yellow solid,which was used directly for next step without further purification.ES+APCI MS m/z 873.4[M+H]⁺.

Step G:4-[4-[2-(hydroxymethyl)piperazin-1-yl]-2-(3-morpholinopropoxy)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl]naphthalen-2-ol

A mixture of tert-butyl3-[[tert-butyl(diphenyl)silyl]oxymethyl]-4-[7-(3-hydroxy-1-naphthyl)-2-(3-morpholinopropoxy)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(130 mg, 149 umol), pyridine hydrofluoride (123 mg, 744 umol, 112 uL,60.0% purity) in THE (1.5 mL) was stirred at 25° C. for 12 hours underN₂ atmosphere. The reaction mixture was concentrated under reducedpressure to dryness. The residue was purified by reverse phase HPLC (TFAcondition; MeCN in H₂O; 0˜30%, flow rate; 40 mL/mins). The desiredfractions were concentrated under reduced pressure to give4-[4-[2-(hydroxymethyl)piperazin-1-yl]-2-(3-morpholinopropoxy)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl]naphthalen-2-ol(84 mg, 104 umol, 69.6% yield, 94.1% purity, 2TFA) as a yellowsemisolid. ES+APCI MS m/z 535.3 [M+H]⁺.

Step H:1-[3-(hydroxymethyl)-4-[7-(3-hydroxy-1-naphthyl)-2-(3-morpholinopropoxy)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one

To a mixture of4-[4-[2-(hydroxymethyl)piperazin-1-yl]-2-(3-morpholinopropoxy)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl]naphthalen-2-ol(84.0 mg, 114 umol, 2TFA), DIEA (36.9 mg, 285 umol, 49.8 uL) in DCM (3mL) was added prop-2-enoyl prop-2-enoate (8.63 mg, 68.44 umol) drop wiseat −40° C., and then stirred at −40° C. for 0.5 hours under N₂atmosphere. The reaction mixture was quenched by addition MeOH (0.5 mL)and concentrated under reduced pressure to dryness. The residue waspurified by prep-HPLC (column: Venusil XBP C8 150*25*10 um; mobilephase: [water (0.225% Formic Acid)-ACN]; B %: 10%-40%, 10 min). Thedesired fractions were collected and lyophilized to dryness to give1-[3-(hydroxymethyl)-4-[7-(3-hydroxy-1-naphthyl)-2-(3-morpholinopropoxy)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one(9.75 mg, 14.5 umol, 12.7% yield, 94.4% purity, Formic Acid Salt) as ayellow solid. ES+APCI MS m/z 589.3[M+H]⁺.

Example 1691-[3-(hydroxymethyl)-4-[7-(3-hydroxy-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one

Step A: tert-butyl4-[7-benzyl-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-3-[[tert-butyl(diphenyl)silyl]oxymethyl]piperazine-1-carboxylate:To a mixture of tert-butyl4-(7-benzyl-2-chloro-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl)-3-[[tert-butyl(diphenyl)silyl]oxymethyl]piperazine-1-carboxylate(495 mg, 694 umol), [(2S)-1-methylpyrrolidin-2-yl]methanol (160 mg, 1.39mmol, 165 uL) and sodium tert-butoxide (200 mg, 2.08 mmol) in toluene(25 mL) was added BINAP (86.5 mg, 139 umol) and Pd₂(dba)₃ (63.6 mg, 69.5umol). The mixture was bubbled with nitrogen atmosphere and stirred at80° C. for 6 h. The reaction mixture was diluted with water (10 mL) andextracted with ethyl acetate (2×15 mL). The combined organic layers werewashed with water (2×30 mL), dried over Na₂SO₄, filtered andconcentrated under reduced pressure to give a residue. The residue waspurified by column chromatography (SiO₂, Petroleum ether/Ethylacetate=30/1 to 1:1) to give tert-butyl4-[7-benzyl-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-3-[[tert-butyl(diphenyl)silyl]oxymethyl]piperazine-1-carboxylate(207 mg, 262 umol, 37.7% yield) as a yellow solid. ¹H NMR (400 MHz,chloroform-d) 6=7.62-7.53 (m, 4H), 7.43-7.28 (m, 11H), 4.42-4.29 (m,1H), 4.26-3.87 (m, 4H), 3.81 (br d, J=13.2 Hz, 2H), 3.75-3.60 (m, 4H),3.44 (dd, J=1.6, 17.2 Hz, 1H), 3.24-3.04 (m, 3H), 2.96 (br s, 1H), 2.75(br s, 3H), 2.49 (s, 3H), 2.43-2.28 (m, 2H), 2.10-1.96 (m, 2H),1.91-1.80 (m, 1H), 1.80-1.67 (m, 2H), 1.43 (s, 9H), 1.02-0.89 (m, 9H).

Step B: tert-butyl 3-[[tert-butyl(diphenyl)silyl]oxymethyl]-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate:NH₃ was bubbled in methanol (30 mL) at −40° C. for 30 minutes. To asolution of tert-butyl4-[7-benzyl-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-3-[[tert-butyl(diphenyl)silyl]oxymethyl]piperazine-1-carboxylate(530 mg, 670 umol) in above mixture was added dry 10% Pd/C (0.30 g)under N₂. The suspension was degassed under vacuum and purged with H₂several times. The mixture was stirred at 40° C. for 10 hours under 15psi of H₂. The reaction mixture was filtered and concentrated underreduced pressure to give tert-butyl 3-[[tert-butyl(diphenyl)silyl]oxymethyl]-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(394 mg, 427 umol, 63.8% yield) as a yellow solid. ¹H NMR (400 MHz,chloroform-d) 6=7.57 (br t, J=6.0 Hz, 4H), 7.43-7.33 (m, 6H), 4.43 (brdd, J=5.2, 10.4 Hz, 1H), 4.32-4.00 (m, 4H), 3.99-3.89 (m, 2H), 3.88-3.65(m, 4H), 3.27-2.89 (m, 6H), 2.81 (br d, J=8.4 Hz, 2H), 2.56-2.50 (m,3H), 2.42 (br d, J=16.8 Hz, 2H), 2.13-2.03 (m, 1H), 1.88 (br d, J=6.8Hz, 1H), 1.79 (br d, J=5.2 Hz, 2H), 1.43 (s, 9H), 0.95 (br s, 9H).

Step C: tert-butyl4-[7-(3-benzyloxy-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-3-[[tert-butyl(diphenyl)silyl]oxymethyl]piperazine-1-carboxylate: A mixture of tert-butyl3-[[tert-butyl(diphenyl)silyl]oxymethyl]-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(0.16 g, 228 umol), 3-benzyloxy-1-bromo-naphthalene (143 mg, 457 umol),[2-(2-aminoethyl)phenyl]-chloro-palladium;dicyclohexyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphane (16.9 mg,22.8 umol) and t-BuONa (43.9 mg, 457 umol) in toluene (4 mL) was stirredat 70° C. for 12 hours under N₂. The mixture was diluted with water(5.00 mL) and extracted with ether acetate (3×10 mL). The combinedorganics were washed with saturated sodium chloride (10 mL), dried overNa₂SO₄, filtered and concentrated under vacuum. The residue was purifiedby reversed phase flash [water (formic acid, 0.1%)/acetonitrile] to givetert-butyl4-[7-(3-benzyloxy-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-3-[[tert-butyl(diphenyl)silyl]oxymethyl]piperazine-1-carboxylate(0.15 g, 157 umol, 68.9% yield) as a yellow solid. ES+APCI MS m/z933.1[M+H]⁺.

Step D:tert-butyl3-[[tert-butyl(diphenyl)silyl]oxymethyl]-4-[7-(3-hydroxy-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate:NH₃ was bubbled into methanol (10 mL) at −78° C. for 30 minutes.tert-butyl4-[7-(3-benzyloxy-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-3-[[tert-butyl(diphenyl)silyl]oxymethyl]piperazine-1-carboxylate(0.10 g, 107 umol) and dry 10% Pd/C (0.01 g) were added and the mixturewas stirred at 10° C. for 1 hour under 15 psi of H₂. The slurry wasfiltered through a pad of celite and the filtrate concentrated undervacuum to give tert-butyl3-[[tert-butyl(diphenyl)silyl]oxymethyl]-4-[7-(3-hydroxy-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(0.09 g, crude) as a yellow oil and used into next step without furtherpurification. ES+APCI MS m/z 843.0 [M+H]⁺.

Step E:4-[4-[2-(hydroxymethyl)piperazin-1-yl]-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl]naphthalen-2-ol:A mixture of tert-butyl3-[[tert-butyl(diphenyl)silyl]oxymethyl]-4-[7-(3-hydroxy-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(0.04 g, crude) and pyridine; hydrofluoride (118 mg, 712 umol, 106 uL)in dichloromethane (2 mL) was stirred at 0° C. for 1 hour and stirred at10° C. for 12 hours. The pH of the mixture was adjusted to pH>7 byaddition of saturated sodium bicarbonate solution (3.00 mL) andconcentrated under vacuum. The residue was purified by columnchromatography (Al₂O₃, dichloromethane/methanol=5/1) to give4-[4-[2-(hydroxymethyl)piperazin-1-yl]-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl]naphthalen-2-ol(0.04 g, crude) as a yellow solid. ES+APCI MS m/z 505.2 [M+H]⁺.

Step F:1-[3-(hydroxymethyl)-4-[7-(3-hydroxy-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one:To a solution of4-[4-[2-(hydroxymethyl)piperazin-1-yl]-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl]naphthalen-2-ol(0.02 g, crude) and TEA (40.1 mg, 396 umol, 55.17 uL) in dichloromethane(2 mL) was added prop-2-enoyl prop-2-enoate (999 ug, 7.93 umol) at −40°C., then the mixture was stirred at −40° C. for 0.5 h. The mixture wasquenched by addition of methanol (0.10 mL) and concentrated undervacuum. The residue was purified by column chromatography (Al₂O₃,dichloromethane/methanol=5/1). The desired fractions were collected andconcentrated under vacuum. The residue was purified by prep-HPLC(column: Phenomenex Gemini 150*25 mm*10 um; mobile phase: [water (10 mMNH4HCO3)-ACN]; B %: 38%-68%, 3 min). The desired fractions werecollected and lyophilized to give1-[3-(hydroxymethyl)-4-[7-(3-hydroxy-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one(1.08 mg, 1.73 umol). ES+APCI MS m/z 559.5 [M+H]⁺.

Example 1702-(1-acryloyl-4-(2-(2-(dimethylamino)ethoxy)-7-(3-hydroxynaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

Step A:1-(tert-butyl)2-methyl4-(7-benzyl-2-chloro-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1,2-dicarboxylate

To a solution of 7-benzyl-2,4-dichloro-6,8-dihydro-5H-pyrido [3,4-d]pyrimidine (5.00 g, 17.0 mmol) and 1-tert-butyl2-methylpiperazine-1,2-dicarboxylate (4.24 g, 17.3 mmol) in DMSO (80 mL)was added DIEA (5.49 g, 42.5 mmol, 7.42 mL). After stirring at 55° C.for 12 hours, the mixture was diluted with ethyl acetate (100 mL),washed with brine (3×150 mL), dried over Na₂SO₄, filtered andconcentrated under vacuum. The residue was purified by columnchromatography (SiO₂, PE/EA=3/1) to give 1-tert-butyl 2-methyl4-(7-benzyl-2-chloro-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl)piperazine-1,2-dicarboxylate (8.00 g, 15.9 mmol, 93.8%yield) as a yellow oil. ES+APCI MS m/z 502.1[M+H]⁺.

Step B: 1-(tert-butyl) 2-methyl4-(7-benzyl-2-(2-(dimethylamino)ethoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl) piperazine-1,2-dicarboxylate

A mixture of 1-tert-butyl 2-methyl4-(7-benzyl-2-chloro-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl)piperazine-1,2-dicarboxylate (8.00 g, 15.9 mmol),2-(dimethylamino)ethanol (2.84 g, 31.9 mmol, 3.19 mL), Cs₂CO₃ (13.0 g,39.8 mmol), Pd(OAc)₂ (537 mg, 2.39 mmol) and BINAP (1.98 g, 3.19 mmol)in toluene (30 mL) was stirred at 110° C. for 3 hours under nitrogen.The mixture was diluted with water (30 mL) and then extracted with ethylacetate (3×50 mL). The extracts were washed with brine (1×100 mL), driedover Na₂SO₄, filtered and concentrated under vacuum. The residue waspurified by reverse phase HPLC (TFA, 0.1%) to give 1-tert-butyl 2-methyl4-[7-benzyl-2-[2-(dimethylamino)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1,2-dicarboxylate(6.00 g, 10.8 mmol, 67.9% yield) as a yellow solid. ES+APCI MS m/z555.3[M+H]⁺.

Step C: 1-tert-butyl 2-methyl4-[2-[2-(dimethylamino)ethoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1,2-dicarboxylate

A mixture of 1-tert-butyl 2-methyl 4-[7-benzyl-2-[2-(dimethylamino)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1,2-dicarboxylate(6.00 g, 10.8 mmol) and 10% Pd/C (600 mg, 10.8 mmol) in MeOH (100 mL)was stirred at 40° C. for 12 hours under H₂ at 50 psi. The mixture wasfiltered and the filtrate was concentrated under vacuum to give1-tert-butyl 2-methyl4-[2-[2-(dimethylamino)ethoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1,2-dicarboxylate(4.50 g, crude) was obtained as a yellow solid. ES+APCI MS m/z465.3[M+H]⁺.

Step D: 1-tert-butyl 2-methyl4-[7-(3-benzyloxy-1-naphthyl)-2-[2-(dimethylamino)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1,2-dicarboxylate

A mixture of 1-tert-butyl 2-methyl4-[2-[2-(dimethylamino)ethoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1,2-dicarboxylate(2.90 g, 6.24 mmol), 3-benzyloxy-1-bromo-naphthalene (2.54 g, 8.12mmol), Pd₂(dba)₃ (857 mg, 936 umol), RuPhos (728 mg, 1.56 mmol) andCs₂CO₃ (5.08 g, 15.6 mmol) in 1,4-dioxane (150 mL) was stirred at 85° C.for 5 hours under N₂. The mixture was diluted with water (100 mL),extracted with DCM (1×200 mL). The extracts were, washed with brine(1×300 mL), dried over Na₂SO₄, filtered and concentrated under vacuum.The residue was purified by reverse phase HPLC (TFA, 0.1%) to give1-tert-butyl 2-methyl4-[7-(3-benzyloxy-1-naphthyl)-2-[2-(dimethylamino)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1,2-dicarboxylate(3.50 g, 5.02 mmol, two steps 72.5% yield) as a brown solid. ES+APCI MSm/z 697.3 [M+H]⁺.

Step E: tert-butyl4-[7-(3-benzyloxy-1-naphthyl)-2-[2-(dimethylamino)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(hydroxymethyl)piperazine-1-carboxylate

To a solution of 1-tert-butyl 2-methyl4-[7-(3-benzyloxy-1-naphthyl)-2-[2-(dimethylamino)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1,2-dicarboxylate(1.00 g, 1.44 mmol) in THE (10 mL) was added LiAlH₄ (219 mg, 5.76 mmol)in portions at −60° C. After stirring for 2 hours, the mixture wasquenched with saturated sodium sulfate solution (0.3 mL), filtered andthe filter cake washed with DCM (100 mL). The combined filtrate wasconcentrated under vacuum to give tert-butyl4-[7-(3-benzyloxy-1-naphthyl)-2-[2-(dimethylamino)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(hydroxymethyl)piperazine-1-carboxylate (750 mg, 1.12mmol, 77.8% yield) as a yellow solid. ES+APCI MS m/z 669.3 [M+H]⁺.

Step F:2-[4-[7-(3-benzyloxy-1-naphthyl)-2-[2-(dimethylamino)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile

A mixture of tert-butyl4-[7-(3-benzyloxy-1-naphthyl)-2-[2-(dimethylamino)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(hydroxymethyl)piperazine-1-carboxylate (100 mg, 149 umol), TBAI (11.1 mg, 29.9 umol),1-(p-tolylsulfonyl)imidazole (79.9 mg, 359 umol), NaCN (0.12 g, 2.45mmol), and TEA (37.8 mg, 374 umol, 51.8 uL) in DMF was stirred at 155°C. for 6 hours. The mixture was concentrated under vacuum, diluted withwater (1×5 mL) and then extracted with ethyl acetate (3×10 mL). Theextracts were washed with brine (1×20 mL), dried over Na₂SO₄, filteredand concentrated under vacuum. The residue was purified by prep-HPLCcolumn: Phenomenex Gemini C18 250*50 mm*10 um; mobile phase: [water(0.05% ammonia hydroxide v/v)-ACN]; B %: 50%-70%, 28 MIN) to give2-[4-[7-(3-benzyloxy-1-naphthyl)-2-[2-(dimethylamino)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(160 mg, 277 umol, 37.1% yield) as a yellow solid. ES+APCI MS m/z578.5[M+H]⁺.

Step G:2-[4-[7-(3-benzyloxy-1-naphthyl)-2-[2-(dimethylamino)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile

To a solution of2-[4-[7-(3-benzyloxy-1-naphthyl)-2-[2-(dimethylamino)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(60 mg, 104 umol) and DIEA (67.1 mg, 519 umol, 90.7 uL) in DCM (2 mL)was added prop-2-enoyl prop-2-enoate (13.1 mg, 104 umol) at 0° C. Afterstirred at 10° C. for 4 hours, the mixture was quenched with MeOH (0.1mL), then concentrated under vacuum. The residue was purified by columnchromatography (SiO₂, DCM/MeOH 10/1) to give2-[4-[7-(3-benzyloxy-1-naphthyl)-2-[2-(dimethylamino)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile (40.0mg, 63.3 umol, 61.0% yield) as a yellow oil. ES+APCI MS m/z 632.3[M+H]⁺.

Step H:2-[4-[2-[2-(dimethylamino)ethoxy]-7-(3-hydroxy-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile

To a solution of2-[4-[7-(3-benzyloxy-1-naphthyl)-2-[2-(dimethylamino)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile(30 mg, 47.5 umol) in DCM (2 mL) was added BBr₃ (35.7 mg, 142 umol, 13.7uL) at −78° C. under 0.5 h. The mixture was warmed up to 0° C. andstirred for 2 hours. The mixture was concentrated under vacuum and thenquenched with saturated sodium bicarbonate solution at −78-0° C. Themixture was purified by column chromatography (Al₂O₃, DCM/MeOH=5/1),then further purified by prep-HPLC (column: Gemini 150*25 5u; mobilephase: [water (0.05% ammonia hydroxide v/v)-ACN]; B %: 30%-60%, 12 min).The desired fractions were collected and lyophilized to give2-[4-[2-[2-(dimethylamino)ethoxy]-7-(3-hydroxy-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile(810 ug, 1.46 umol, 3.07% yield, 97.5% purity) as a yellow solid.ES+APCI MS m/z 542.5 [M+H]⁺.

Example 1711-(4-(2-(2-(dimethylamino)ethoxy)-7-(3-hydroxynaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2-(2-hydroxyethyl)piperazin-1-yl)prop-2-en-1-one

Step A: Ethyl 2-(3-oxopiperazin-2-yl)acetate

To a solution of diethyl (E)-but-2-enedioate (30.2 g, 175 mmol, 28.8 mL)in i-PrOH (300 mL) was added ethane-1,2-diamine (11.0 g, 183 mmol, 12.2mL). After stirring at 25° C. for 12 hours, the reaction mixture wasconcentrated under reduced pressure to dryness. The crude white solidwas washed with MTBE (500 mL) and dried under vacuum to give ethyl2-(3-oxopiperazin-2-yl)acetate (26.0 g, 140 mmol, 79.6% yield, 100%purity) as a white solid. ¹H NMR (400 MHz, Chloroform-d) 6=6.55 (br s,1H), 4.15 (q, J=6.8 Hz, 2H), 3.80-3.72 (m, 1H), 3.47 (dt, J=4.8, 11.2Hz, 1H), 3.36-3.22 (m, 1H), 3.18-3.08 (m, 1H), 3.07-2.95 (m, 2H),2.76-2.70 (m, 1H), 1.25 (t, J=7.2 Hz, 3H).

Step B: Ethyl2-[1-[(4-methoxyphenyl)methyl]-3-oxo-piperazin-2-yl]acetate

To a mixture of ethyl 2-(3-oxopiperazin-2-yl)acetate (23.6 g, 127 mmol)in methanol (400 mL) was added 4-methoxybenzaldehyde (18.9 g, 139 mmol,16.9 mL) and CH₃COOH (15.2 g, 253 mmol, 14.5 mL) at 0° C. After stirringat 0° C. for 1 hour, the reaction mixture was cooled to −10° C. NaBH₃CN(23.9 g, 380 mmol) was added to the mixture in portions and the reactionmixture was warmed up to 15° C. and stiring for another 11 hours. Thereaction was quenched by adding water (400 ML) and extracted with DCM(2×300 mL). The combined organic layers were dried over Na₂SO₄, filteredand concentrated. The residue was re-dissolved with ethyl acetate (300mL), then washed with 0.5 M HCl solution (2×200 mL). The aqueous phasewas adjusted to pH 7 8 with Na₂CO₃ solid, then extracted with DCM (2×300mL). The combined organic layers were dried over Na₂SO₄, filtered andconcentrated to give ethyl2-[1-[(4-methoxyphenyl)methyl]-3-oxo-piperazin-2-yl]acetate (27.2 g,87.6 mmol, 69.0% yield, 98.5% purity) as colorless oil. ES+APCI MS m/z307.1 [M+H]⁺.

Step C: 2-[1-[(4-methoxyphenyl)methyl]piperazin-2-yl]ethanol

To a mixture of ethyl2-[1-[(4-methoxyphenyl)methyl]-3-oxo-piperazin-2-yl]acetate (27.2 g,88.8 mmol) in THE (500 mL) was added LiAlH₄ (10.1 g, 266 mmol) inportions at 0° C. After stirring at 0° C. for 1 hour, the reactionmixture was heated to 70° C. and stirred for 11 hours. After completion,the reaction was quenched with sat. Na₂SO₄ aqueous (40 mL), filtered andthen concentrated. The product2-[1-[(4-methoxyphenyl)methyl]piperazin-2-yl]ethanol (20 g, crude) wasobtained as yellow oil. ES+APCI MS m/z 251.1 [M+H]⁺.

Step D: tert-butyl-[2-[1-[(4-methoxyphenyl)methyl]piperazin-2-yl]ethoxyl]-diphenyl-silane

To a mixture of 2-[1-[(4-methoxyphenyl)methyl]piperazin-2-yl]ethanol (20g, crude) in THF (300 mL) was added NaH (15.9 g, 399 mmol, 60% purity)at 0° C. in portions, then a solution of TBDPSCl (65.9 g, 239 mmol, 61.6mL) in THE (100 mL) was added. The mixture was warmed up to 15° C. andstirred for a further 12 hours. After completion, the reaction waspoured into NH₄Cl solution (300 mL), and extracted with DCM (2×300 mL).The combined organic layers were dried over Na₂SO₄, filtered andconcentrated. The residue was purified by column chromatography (SiO₂,Petroleum ether: Ethyl acetate 3/1 to Dichloromethane/Methanol 10/1) togive tert-butyl-[2-[1-[(4-methoxyphenyl)methyl]piperazin-2-yl]ethoxy]-diphenyl-silane (29.5 g, 59.9 mmol, two steps35%, 99.2% purity) as yellow oil. ES+APCI MS m/z 489.4[M+H]⁺.

Step E: tert-butyl3-[2-[tert-butyl(diphenyl)silyl]oxyethyl]-4-[(4-methoxyphenyl)methyl]piperazine-1-carboxylate

To a mixture of tert-butyl-[2-[1-[(4-methoxyphenyl)methyl]piperazin-2-yl]ethoxy]-diphenyl-silane (11.0 g, 22.5 mmol) inMeOH (200 mL) was added TEA (6.83 g, 67.5 mmol, 9.36 mL) and (Boc)₂₀(9.82 g, 45.0 mmol, 10.3 mL). After stirring at 15° C. for 3 hours, thereaction was concentrated. The residue was purified by columnchromatography (SiO₂, Petroleum ether: Ethyl acetate I/O to 5/1) to givetert-butyl3-[2-[tert-butyl(diphenyl)silyl]oxyethyl]-4-[(4-methoxyphenyl)methyl]piperazine-1-carboxylate (11.0 g, 18.7 mmol, 82.9% yield, 100% purity)as colorless oil. ES+APCI MS m/z 589.4 [M+H]⁺.

Step F: tert-butyl 3-[2-tert-butyl(diphenyl)silyl]oxyethyl]piperazine-1-carboxylate

To a mixture of tert-butyl3-[2-[tert-butyl(diphenyl)silyl]oxyethyl]-4-[(4-methoxyphenyl)methyl]piperazine-1-carboxylate(9.00 g, 15.3 mmol) in MeOH (150 mL) was added 10% Pd/C (849 umol). Thesuspension was degassed under vacuum and purged with H₂ for three times.The mixture was stirred under H₂ (50 Psi) at 40° C. for 18 hours. Aftercompletion, the reaction mixture was filtered through a Celite plug andthe filtrate was concentrated. The residue was purified by columnchromatography (SiO₂, Petroleum ether/Ethyl acetate 10/1 to 3:1) to givetert-butyl 3-[2-[tert-butyl(diphenyl)silyl]oxyethyl]piperazine-1-carboxylate (5.80 g, 12.2 mmol, 79.5% yield,98.2% purity) as colorless oil. ES+APCI MS m/z 469.4 [M+H]⁺.

Step G:2-[4-(7-benzyl-2-chloro-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl)-1-[(4-methoxyphenyl)methyl]piperazin-2-yl]ethoxy-tert-butyl-diphenyl-silane

A mixture of 7-benzyl-2,4-dichloro-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine (4.00 g, 13.6 mmol),tert-butyl-[2-[1-[(4-methoxyphenyl)methyl]piperazin-2-yl]ethoxy]-diphenyl-silane (6.98 g, 14.3 mmol) and DIEA(4.39 g, 34.0 mmol, 5.93 mL) in DMSO (80 mL) was degassed and purgedwith N₂ for 3 times, and the mixture was heated to at 55° C. and stirredfor 12 hours under N₂ atmosphere. The reaction mixture was diluted withwater (300 mL) and extracted with ethyl acetate (3×200 mL). The combinedorganic layers were washed with brine (3×200 mL), dried over Na₂SO₄,filtered and concentrated under reduced pressure to dryness. The residuewas purified by column chromatography (SiO₂, Petroleum ether/Ethylacetate 1/0 to 3/1) to give2-[4-(7-benzyl-2-chloro-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl)-1-[(4-methoxyphenyl)methyl]piperazin-2-yl]ethoxy-tert-butyl-diphenyl-silane(9.00 g, 11.7 mmol, 86.0% yield, 97.0% purity) as a yellow oil. ES+APCIMS m/z 746.4[M+H]⁺.

Step H:2-[[7-benzyl-4-[3-[2-[tert-butyl(diphenyl)silyl]oxyethyl]-4-[(4-methoxyphenyl)methyl]piperazin-1-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-2-yl]oxy]-N,N-dimethyl-ethanamine

A mixture of 2-(dimethylamino)ethanol (2.39 g, 26.8 mmol, 2.69 mL),2-[4-(7-benzyl-2-chloro-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl)-1-[(4-methoxyphenyl)methyl]piperazin-2-yl]ethoxy-tert-butyl-diphenyl-silane(8.00 g, 10.7 mmol), Pd(OAc)₂ (361 mg, 1.61 mmol), BINAP (1.34 g, 2.14mmol) and Cs₂CO₃ (8.73 g, 26.8 mmol) in toluene (100 mL) was degassedand purged with N₂ for 3 times. The mixture was heated to 110° C. andstirred for 3 hours under N₂ atmosphere. The reaction mixture wasfiltered and the filtrate was concentrated under reduced pressure todryness. The residue was purified by column chromatography (SiO₂,DCM/MeOH 50/1 to 10/1) to give2-[[7-benzyl-4-[3-[2-[tert-butyl(diphenyl)silyl]oxyethyl]-4-[(4-methoxyphenyl)methyl]piperazin-1-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-2-yl]oxy]-N,N-dimethyl-ethanamine(6.50 g, crude) as a yellow semisolid. ES+APCI MS m/z 799.4 [M+H]⁺.

Step I: 2-[4-[7-benzyl-2-[2-(dimethylamino)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]ethanol

2-[4-[7-benzyl-2-[2-(dimethyl amino)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]ethanol: A solution of2-[[7-benzyl-4-[3-[2-[tert-butyl(diphenyl)silyl]oxyethyl]-4-[(4-methoxyphenyl)methyl]piperazin-1-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-2-yl]oxy]-N,N-dimethyl-ethanamine(6.50 g, crude) in TFA (80 mL) was stirred at 80° C. for 12 hours. Thereaction mixture was concentrated under reduced pressure to dryness andthe residue was re-dissolved into DCM (300 mL) and washed with water(200 mL). The water phase was collected and basified with saturatedNaHCO₃ aqueous to pH ˜8 and then extracted with DCM (3×200 mL). Thecombined organic phase was dried over Na₂SO₄, filtered and concentratedunder reduced pressure to give 2-[4-[7-benzyl-2-[2-(dimethylamino)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]ethanol (3.00 g, crude) as a yellowsemisolid, which was used directly for next step without furtherpurification.

Step J:2-[[7-benzyl-4-[3-[2-[tert-butyl(diphenyl)silyl]oxyethyl]piperazin-1-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-2-yl]oxy]-N,N-dimethyl-ethanamine

A solution of2-[4-[7-benzyl-2-[2-(dimethylamino)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]ethanol(3.0 g, crude) in THE (40 mL) was added NaH (1.36 g, 34.1 mmol, 60.0%purity) at 0° C. After stirring for 30 minutes, TBDPSCl (2.81 g, 10.2mmol, 2.63 mL) was added by portions. The mixture was warmed to 25° C.and stirred for another 2 hours under N₂ atmosphere. The reactionmixture was quenched by addition water (30 mL) at 0° C. and extractedinto ethyl acetate (3×100 mL). The combined organic layers were washedwith brine (3×100 mL), dried over Na₂SO₄, filtered and concentratedunder reduced pressure to dryness to give2-[[7-benzyl-4-[3-[2-[tert-butyl(diphenyl)silyl]oxyethyl]piperazin-1-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-2-yl]oxy]-N,N-dimethyl-ethanamine(6.00 g, crude) as a yellow oil, which was used directly for next stepwithout further purification. ES+APCI MS m/z 679.4 [M+H]⁺.

Step K:tert-butyl4-[7-benzyl-2-[2-(dimethylamino)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-[2-[tert-butyl(diphenyl)silyl]oxyethyl]piperazine-1-carboxylate

A mixture of 2-[[7-benzyl-4-[3-[2-[tert-butyl(diphenyl)silyl]oxyethyl]piperazin-1-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-2-yl]oxy]-N,N-dimethyl-ethanamine(6.0 g, crude), Boc20 (18.5 g, 84.8 mmol, 19.5 mL) in MeOH (3 mL) wasdegassed and purged with N₂ for 3 times. The mixture was heated to 80°C. and stirred for 3 hours under N₂ atmosphere. The reaction mixture wasconcentrated under reduced pressure to dryness. The residue was purifiedby column chromatography (SiO₂, DCM/MeOH I/O to 10/1) to givetert-butyl4-[7-benzyl-2-[2-(dimethylamino)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-[2-[tert-butyl(diphenyl)silyl]oxyethyl]piperazine-1-carboxylate(3.10 g, 3.28 mmol, four steps 30.7% yield, 82.2% purity) as asemisolid. ES+APCI MS m/z 779.4 [M+H]⁺.

Step L:tert-butyl2-[2-[tert-butyl(diphenyl)silyl]oxyethyl]-4-[2-[2-(dimethylamino)ethoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate

To a solution oftert-butyl4-[7-benzyl-2-[2-(dimethylamino)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-[2-[tert-butyl(diphenyl)silyl]oxyethyl]piperazine-1-carboxylate(3.10 g, 3.28 mmol, 82.2% purity) in MeOH (60 mL) was added Pd—C (10%, 2g) under N₂. The suspension was degassed under vacuum and purged with H₂for three times. The mixture was stirred under H₂ (50 psi) at 50° C. for36 hours. The reaction mixture was filtered and concentrated underreduced pressure to dryness to givetert-butyl2-[2-[tert-butyl(diphenyl)silyl]oxyethyl]-4-[2-[2-(dimethylamino)ethoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(2.20 g, 2.75 mmol, 83.8% yield, 86.0% purity) as a yellow solid, whichwas used directly for next step without further purification. ES+APCI MSm/z 689.4 [M+H]⁺.

Step M:tert-butyl4-[7-(3-benzyloxy-1-naphthyl)-2-[2-(dimethylamino)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-[2-[tert-butyl(diphenyl)silyl]oxyethyl]piperazine-1-carboxylate

A mixture oftert-butyl2-[2-[tert-butyl(diphenyl)silyl]oxyethyl]-4-[2-[2-(dimethylamino)ethoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(1.85 g, 2.69 mmol), 3-benzyloxy-1-bromo-naphthalene (1.09 g, 3.49mmol), Cs₂CO₃ (2.19 g, 6.71 mmol),[2-(2-aminophenyl)phenyl]palladium(1+);dicyclohexyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphane;methanesulfonate (341 mg, 403 umol) in toluene (40 mL) was degassed andpurged with N₂ for 3 times, and the mixture was stirred at 65° C. for 10hours under N₂ atmosphere. After completion, the reaction mixture wasfiltered and concentrated under reduced pressure to dryness. The residuewas purified by column chromatography (SiO₂, DCM/MeOH I/O to 10/1) togivetert-butyl4-[7-(3-benzyloxy-1-naphthyl)-2-[2-(dimethylamino)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-[2-[tert-butyl(diphenyl)silyl]oxyethyl]piperazine-1-carboxylate(1.85 g, 1.69 mmol, 63.2% yield, 84.3% purity) as a yellow solid.ES+APCI MS m/z 922.5 [M+H]⁺.

Step N:1-[4-[7-(3-benzyloxy-1-naphthyl)-2-[2-(dimethylamino)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-[2-[tert-butyl(diphenyl)silyl]oxyethyl]piperazin-1-yl]prop-2-en-1-one

To a solution of tert-butyl4-[7-(3-benzyloxy-1-naphthyl)-2-[2-(dimethylamino)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-[2-[tert-butyl(diphenyl)silyl]oxyethyl]piperazine-1-carboxylate(500 mg, 543 umol), 2,6-lutidine (700 mg, 6.51 mmol, 759 uL) in DCM (10mL) was added TMSOTf (724 mg, 3.26 mmol, 588 uL). After stirring at 40°C. for 2 hours under N₂ atmosphere, the reaction mixture was cooled to−40° C. and prop-2-enoyl prop-2-enoate (137 mg, 1.09 mmol) was addedportionwise. The reaction mixture was warmed to 25° C. and stirred foranother 12 hours under N₂ atmosphere. After completion, the reactionmixture was purified directly by column chromatography (SiO₂, DCM/MeOH30/1 to 10/1) to give1-[4-[7-(3-benzyloxy-1-naphthyl)-2-[2-(dimethylamino)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-[2-[tert-butyl(diphenyl)silyl]oxyethyl]piperazin-1-yl]prop-2-en-1-one(256 mg, 226 umol, 41.6% yield, 77.2% purity) as a semisolid. ES+APCI MSm/z 875.5 [M+H]⁺.

Step O:1-[4-[2-[2-(dimethylamino)ethoxy]-7-(3-hydroxy-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(2-hydroxyethyl)piperazin-1-yl]prop-2-en-1-one

To a solution of 1-[4-[7-(3-benzyloxy-1-naphthyl)-2-[2-(dimethylamino)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-[2-[tert-butyl(diphenyl)silyl]oxyethyl]piperazin-1-yl]prop-2-en-1-one(133 mg, 152 umol) in DCM (5.00 mL) was added BBr₃ (571 mg, 2.28 mmol,220 uL) dropwise at −40° C. The reaction mixture was warmed to 0° C. andstirred for 3 hours. The mixture was concentrated under reduced pressureto dryness. The crude material was washed with MTBE (25 mL) and thesolid was collected. The solid was washed with saturated NaHCO₃ solution(0.5 mL) to pH ˜8 at 0° C. then dissolved in MeOH (3 mL). The mixturewas directly purified by prep-HPLC (column: Boston Green ODS 150*30 5u;mobile phase: [water (0.225% Formic Acid)-ACN]; B %: 15%-39%, 10 min) togive1-[4-[2-[2-(dimethylamino)ethoxy]-7-(3-hydroxy-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(2-hydroxyethyl)piperazin-1-yl]prop-2-en-1-one(16.7 mg, 28.2 umol, 18.5% yield, 99.9% purity, Formic Acid Salt) as ayellow solid. ES+APCI MS m/z 547.3 [M+H]⁺.

Example 1721-(4-(2-(2-(dimethylamino)ethoxy)-7-(3-hydroxynaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-3-(2-hydroxyethyl)piperazin-1-yl)prop-2-en-1-one

Step A:tert-butyl4-(7-benzyl-2-chloro-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl)-3-[2-[tert-butyl(diphenyl)silyl]oxyethyl]piperazine-1-carboxylate:A mixture of 7-benzyl-2,4-dichloro-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine (3.04 g, 10.3 mmol),tert-buty3-[2-[tert-butyl(diphenyl)silyl]oxyethyl]piperazine-1-carboxylate (5.08 g, 10.8 mmol), DIEA (3.34 g, 25.8 mmol,4.51 mL) in DMSO (60 mL) was degassed and purged with N₂ for 3 times.The mixture heated to 55° C. and stirred for 16 hours under a N₂atmosphere. After cooling to room temperature, the reaction mixture wasdiluted with water (100 mL) and extracted with ethyl acetate (3×100 mL).The combined organic layers were washed with brine (3×100 mL), driedover Na₂SO₄, filtered and concentrated under reduced pressure todryness. The residue was purified by column chromatography (SiO₂,Petroleum ether/Ethyl acetate I/O to 3/1) to givetert-butyl4-(7-benzyl-2-chloro-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl)-3-[2-[tert-butyl(diphenyl)silyl]oxyethyl]piperazine-1-carboxylate(3.50 g, 4.53 mmol, 43.9% yield, 94.0% purity) as a yellow semisolid.ES+APCI MS m/z 726.4 [M+H]⁺.

Step B: tert-butyl4-[7-benzyl-2-[2-(dimethylamino)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-3-[2-[tert-butyl(diphenyl)silyl]oxyethyl]piperazine-1-carboxylate:A mixture of 2-(dimethylamino)ethanol (1.07 g, 12.1 mmol, 1.21 mL),tert-butyl4-(7-benzyl-2-chloro-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl)-3-[2-[tert-butyl(diphenyl)silyl]oxyethyl]piperazine-1-carboxylate(3.50 g, 4.82 mmol), Pd(OAc)₂ (162 mg, 723 umol), BINAP (600 mg, 964umol) and Cs₂CO₃ (3.92 g, 12.1 mmol) in toluene (40 mL) was degassed andpurged with N₂ for 3 times. The mixture was heated to 110° C. withstirring for 3 hours under N₂ atmosphere. After cooling to the roomtemperature, the reaction mixture was filtered and concentrated underreduced pressure to dryness. The residue was purified by columnchromatography (SiO₂, DCM/MeOH=I/O to 10/1) to give tert-butyl4-[7-benzyl-2-[2-(dimethylamino)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-3-[2-[tert-butyl(diphenyl)silyl]oxyethyl]piperazine-1-carboxylate(2.30 g, 2.57 mmol, 53.3% yield, 87.0% purity) as a yellow solid.ES+APCI MS m/z 779.5 [M+H]⁺.

Step C: tert-butyl3-[2-[tert-butyl(diphenyl)silyl]oxyethyl]-4-[2-[2-(dimethylamino)ethoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate:To a solution of tert-butyl4-[7-benzyl-2-[2-(dimethylamino)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-3-[2-[tert-butyl(diphenyl)silyl]oxyethyl]piperazine-1-carboxylate (2.30 g, 2.95 mmol) in MeOH (40 mL) was addedPd—C (10%, 1.5 g) under N₂. The suspension was degassed under vacuum andpurged with H₂ several times. After stirring under H₂ (50 psi) at 50° C.for 36 hours, the reaction mixture was filtered and concentrated underreduced pressure to give tert-butyl3-[2-[tert-butyl(diphenyl)silyl]oxyethyl]-4-[2-[2-(dimethylamino)ethoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(1.58 g, 1.83 mmol, 61.9% yield, 79.6% purity) as a colorless oil, whichwas used directly for next step without further purification. ES+APCI MSm/z 689.4 [M+H]⁺.

Step D:tert-butyl4-[7-(3-benzyloxy-1-naphthyl)-2-[2-(dimethylamino)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-3-[2-[tert-butyl(diphenyl)silyl]oxyethyl]piperazine-1-carboxylate: A mixture of tert-butyl3-[2-[tert-butyl(diphenyl)silyl]oxyethyl]-4-[2-[2-(dimethylamino)ethoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate (1.48 g, 2.15 mmol),3-benzyloxy-1-bromo-naphthalene (875 mg, 2.80 mmol), Cs₂CO₃ (1.75 g,5.38 mmol), [2-(2-aminophenyl)phenyl]palladium(1+);dicyclohexyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphane;methanesulfonate (273 mg, 323 umol) in toluene (30 mL) was degassed andpurged with N₂ for 3 times, and then the mixture was stirred at 65° C.for 24 hours under N₂ atmosphere. The reaction mixture was filtered andconcentrated under reduced pressure to dryness. The residue was purifiedby column chromatography (Al₂O₃, DCM/MeOH=1/0 to 20/1) to givetert-butyl4-[7-(3-benzyloxy-1-naphthyl)-2-[2-(dimethylamino)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-3-[2-[tert-butyl(diphenyl)silyl]oxyethyl]piperazine-1-carboxylate(1.20 g, 1.07 mmol, 49.7% yield, 82.0% purity) as a yellow solid.ES+APCI MS m/z 921.4 [M+H]⁺.

Step E: 2-[[7-(3-benzyloxy-1-naphthyl)-4-[2-[2-[tert-butyl(diphenyl)silyl]oxyethyl]piperazin-1-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-2-yl]oxy]-N,N-dimethyl-ethanamine: A mixture oftert-butyl4-[7-(3-benzyloxy-1-naphthyl)-2-[2-(dimethylamino)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-3-[2-[tert-butyl(diphenyl)silyl]oxyethyl]piperazine-1-carboxylate(300 mg, 326 umol) and 2,6-lutidine (419 mg, 3.91 mmol, 455 uL) in DCM(10 mL) was added TMSOTf (434 mg, 1.95 mmol, 353 uL) portionwise at 0°C. The mixture was warmed to 10° C. and stirred for 12 hours under N₂atmosphere. The reaction mixture was purified directly by columnchromatography (Al₂O₃, DCM/MeOH I/O to 50/1) to give2-[[7-(3-benzyloxy-1-naphthyl)-4-[2-[2-[tert-butyl(diphenyl)silyl]oxyethyl]piperazin-1-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-2-yl]oxy]-N,N-dimethyl-ethanamine(210 mg, 229 umol, 70.3% yield, 89.5% purity) as a yellow semi-solid.ES+APCI MS m/z 821.5 [M+H]⁺.

Step F:1-[4-[7-(3-benzyloxy-1-naphthyl)-2-[2-(dimethylamino)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-3-[2-[tert-butyl(diphenyl)silyl]oxyethyl]piperazin-1-yl]prop-2-en-1-one: To a mixture of2-[[7-(3-benzyloxy-1-naphthyl)-4-[2-[2-[tert-butyl(diphenyl)silyl]oxyethyl]piperazin-1-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-2-yl]oxy]-N,N-dimethyl-ethanamine (210 mg, 256 umol) and DIEA(49.6 mg, 384 umol, 67.0 uL) in DCM (10 mL) was added prop-2-enoylprop-2-enoate (33.9 mg, 269 umol) portionwise at −40° C. under nitrogenatmosphere. After stirring for 30 minutes at the same temperature, thereaction mixture was purified directly by column chromatography (Al₂O₃,DCM/MeOH 1/0 to 50/1) to give1-[4-[7-(3-benzyloxy-1-naphthyl)-2-[2-(dimethylamino)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-3-[2-[tert-butyl(diphenyl)silyl]oxyethyl]piperazin-1-yl]prop-2-en-1-one(221 mg, 214 umol, 83.6% yield, 84.7% purity) as a slight yellowsemi-solid. ES+APCI MS m/z 875.4 [M+H]⁺.

Step G:1-[4-[2-[2-(dimethylamino)ethoxy]-7-(3-hydroxy-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-3-(2-hydroxyethyl)piperazin-1-yl]prop-2-en-1-one:A mixture of 1-[4-[7-(3-benzyloxy-1-naphthyl)-2-[2-(dimethylamino)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-3-[2-[tert-butyl(diphenyl)silyl]oxyethyl]piperazin-1-yl]prop-2-en-1-one(221 mg, 253 umol) in DCM (10 mL) was added BBr₃ (949 mg, 3.79 mmol, 365uL) at −40° C. The mixture was stirred at 0° C. for 3 hours under N₂atmosphere. The reaction mixture was concentrated under reduced pressureto dryness. The crude pdt was washed with MTBE (25 mL), saturated NaHCO₃solution (0.5 mL) to pH 8 at 0° C. and dissolved in MeOH (3 mL). Theresulting solution was purified by prep-HPLC (column: Boston Green ODS150*30 5u; mobile phase: [water (0.225% Formic Acid)-ACN]; B %: 11%-41%,10 min) to give1-[4-[2-[2-(dimethylamino)ethoxy]-7-(3-hydroxy-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-3-(2-hydroxyethyl)piperazin-1-yl]prop-2-en-1-one(26.7 mg, 44.0 umol, 17.4% yield, 97.8% purity, Formic Acid Salt) as ayellow solid. ES+APCI MS m/z 547.3 [M+H]⁺.

Example 1731-(4-(7-(3-hydroxy-2-methylnaphthalen-1-yl)-2-(3-morpholinopropoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

1-(4-(7-(3-hydroxy-2-methylnaphthalen-1-yl)-2-(3-morpholinopropoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-onewas prepared according to the procedure for Example 1651-[4-[7-(2-fluoro-3-hydroxy-1-naphthyl)-2-(3-morpholinopropoxy)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-onesubstituting (3-methoxy-2-methyl-1-naphthyl) trifluoromethanesulfonatefor (2-fluoro-3-methoxy-1-naphthyl) trifluoromethanesulfonate in step Fto give the desired product1-(4-(7-(3-hydroxy-2-methylnaphthalen-1-yl)-2-(3-morpholinopropoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-oneas yellow solid (10.4 mg, 13.1% yield, 98.1% purity). ES+APCI MS m/z573.5 [M+H]⁺.

Example 174(R)-1-(4-(2-((5,5-dimethylpyrrolidin-2-yl)methoxy)-7-(3-hydroxynaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Step A: tert-Butyl(5R)-5-(hydroxymethyl)-2,2-dimethyl-pyrrolidine-1-carboxylate

To a solution of(2R)-1-tert-butoxycarbonyl-5,5-dimethyl-pyrrolidine-2-carboxylic acid(500 mg, 2.06 mmol) in anhydrous THF (4 mL) was added BH₃-Me₂S (2 M,1.23 mL) dropwise at 15° C. The reaction was heated at 50° C. for 5minutes. After cooling in an ice-bath, to the mixture was added Methanol(20 mL). The reaction mixture was concentrated under reduced pressure at25° C. tert-Butyl(5R)-5-(hydroxymethyl)-2,2-dimethyl-pyrrolidine-1-carboxylate (400 mg,1.74 mmol, 84.9% yield) was obtained as a white solid.

¹H NMR (400 MHz, methanol-d₄) δ=3.97-3.81 (m, 1H), 3.62 (dd, J=3.6, 10.8Hz, 1H), 3.45-3.33 (m, 1H), 2.02-1.79 (m, 3H), 1.79-1.67 (m, 1H),1.49-1.41 (m, 12H), 1.32 (s, 3H).

Step B: Benzyl4-[7-(3-benzyloxy-1-naphthyl)-2-[[(2R)-1-tert-butoxycarbonyl-5,5-dimethyl-pyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate

To a solution of tert-butyl(5R)-5-(hydroxymethyl)-2,2-dimethyl-pyrrolidine-1-carboxylate (212 mg,926 umol) and benzyl4-[7-(3-benzyloxy-1-naphthyl)-2-methylsulfinyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(300 mg, 463 umol) in THE (10 mL) was added t-BuONa (133 mg, 1.39 mmol).After stirring at 15° C. for 1 hour, the reaction mixture was pouredinto H₂O (20 mL) and extracted with ethyl acetate (20 mL×3). The organicphase was washed with brine (20 mL), dried over anhydrous Na₂SO₄,filtered and concentrated in vacuo. The residue was purified by reversedphase flash [water (0.1% formic acid)/acetonitrile]. The desiredfractions were collected and concentrated under vacuum. Compound benzyl4-[7-(3-benzyloxy-1-naphthyl)-2-[[(2R)-1-tert-butoxycarbonyl-5,5-dimethyl-pyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(110 mg, 129 umol, 28.1% yield, 96% purity) was obtained as a yellowsolid. ES+APCI MS m/z 813.5 [M+H]⁺.

Step C: tert-butyl(5R)-5-[[7-(3-hydroxy-1-naphthyl)-4-piperazin-1-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-2-yl]oxymethyl]-2,2-dimethyl-pyrrolidine-1-carboxylate

NH₃ was bubbled into MeOH (30 mL) at −40° C. for 30 minutes. To asolution of benzyl4-[7-(3-benzyloxy-1-naphthyl)-2-[[(2R)-1-tert-butoxycarbonyl-5,5-dimethyl-pyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(200 mg, 246 umol) in above the mixture (NH₃/MeOH) was added dry Pd—C(10%, 100 mg) under N₂. The suspension was degassed under vacuum andpurged with H₂ several times. The mixture was stirred under H₂ (15 psi)at 15° C. for 1 hour. The catalyst was filtered off and the filtrate wasconcentrated to give the product tert-butyl(5R)-5-[[7-(3-hydroxy-1-naphthyl)-4-piperazin-1-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-2-yl]oxymethyl]-2,2-dimethyl-pyrrolidine-1-carboxylate(150 mg, 244 umol, 99.4% yield, 96% purity) as a yellow solid anddirectly used next step without purification. ES+APCI MS m/z 589.3[M+H]⁺.

Step D: tert-Butyl(5R)-5-[[7-(3-hydroxy-1-naphthyl)-4-(4-prop-2-enoylpiperazin-1-yl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-2-yl]oxymethyl]-2,2-dimethyl-pyrrolidine-1-carboxylate

To a mixture of tert-butyl(5R)-5-[[7-(3-hydroxy-1-naphthyl)-4-piperazin-1-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-2-yl]oxymethyl]-2,2-dimethyl-pyrrolidine-1-carboxylate(130 mg, 221 umol) and DIEA (285 mg, 2.21 mmol, 385 uL) indichloromethane (3 mL) was added a solution of prop-2-enoylprop-2-enoate (22.3 mg, 176 umol) in dichloromethane (1 mL) at −40° C.under nitrogen atmosphere. The mixture was stirred at −40° C. for 1hour. The reaction was quenched by addition of saturated NaHCO₃ (2 mL)aqueous solution. Then the mixture was poured into water (20 mL) andextracted with dichloromethane (20 mL×2). The combined organics wasdried over sodium sulfate, filtered and concentrated in vacuo. Theresidue was purified by column chromatography (SiO₂,dichloromethane/methanol=I/O to 10/1). tert-Butyl(5R)-5-[[7-(3-hydroxy-1-naphthyl)-4-(4-prop-2-enoylpiperazin-1-yl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-2-yl]oxymethyl]-2,2-dimethyl-pyrrolidine-1-carboxylate(140 mg, 217 umol, 98.6% yield) was obtained as a brown oil. ES+APCI MSm/z 643.6 [M+H]⁺.

Step E:1-[4-[2-[[(2R)-5,5-dimethylpyrrolidin-2-yl]methoxy]-7-(3-hydroxy-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one

To a solution of tert-butyl(5R)-5-[[7-(3-hydroxy-1-naphthyl)-4-(4-prop-2-enoylpiperazin-1-yl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-2-yl]oxymethyl]-2,2-dimethyl-pyrrolidine-1-carboxylate(120 mg, 187 umol) in dichloromethane (200 uL) was added TFA (212 mg,1.87 mmol, 138 uL). The mixture was stirred at 15° C. for 1 hour. Thereaction mixture was concentrated under vacuum, then diluted withdichloromethane (5 mL) and adjusted PH=7 by addition saturated NaHCO₃aqueous solution. The mixture was extracted with dichloromethane (10mL×3). The combined organic phase was dried over anhydrous Na₂SO₄,filtered and concentrated in vacuo. The residue was purified byprep-HPLC (column: Phenomenex Gemini 150*25 mm*10 um; mobile phase:[water (0.05% ammonia hydroxide v/v)-ACN]; B %: 45%-75%, 12 min).1-[4-[2-[[(2R)-5,5-dimethylpyrrolidin-2-yl]methoxy]-7-(3-hydroxy-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one(30 mg, 53.6 umol, 28.7% yield, 97% purity) was obtained as yellow solidby lyophilization. ES+APCI MS m/z 543.5 [M+H]⁺.

Example 175(S)-1-(4-(7-(3-hydroxy-2-methylnaphthalen-1-yl)-2-((1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

(S)-1-(4-(7-(3-hydroxy-2-methylnaphthalen-1-yl)-2-((1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-onewas synthesized according to the procedure for Example 165 substitutingtert-butyl4-[2-(3-morpholinopropoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylatefor tert-butyl4-[7-(2-fluoro-3-methoxy-1-naphthyl)-2-(3-morpholinopropoxy)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylateand (2-fluoro-3-methoxy-1-naphthyl) trifluoromethanesulfonate for(3-methoxy-2-methyl-1-naphthyl) trifluoromethanesulfonate in Step F. togive1-[4-[7-(3-hydroxy-2-methyl-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one(10.2 mg, 17.3 umol, 21.4% yield, 100% purity, Formic Acid Salt) as awhite solid. ES+APCI MS m/z 543.4 [M+H]⁺.

Example 1762-[(2S)-4-[2-[2-(dimethylamino)ethoxy]-7-(3-hydroxy-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile

Step A: tert-butyl(3aR)-1-oxo-3a,4,6,7-tetrahydro-3H-oxathiazolo[3,4-a]pyrazine-5-carboxylate

To a solution of imidazole (15.7 g, 231 mmol) in DCM (100 mL) was addedSOCl₂ (8.25 g, 69.4 mmol, 5.03 mL) at 0° C. The reaction mixture wasstirred at 15° C. for 1 hour. To the mixture was added tert-butyl(3R)-3-(hydroxymethyl)piperazine-1-carboxylate (5 g, 23.1 mmol) in DCM(100 mL) at −70° C. The reaction mixture was stirred at 15° C. for 12hour. Upon completion, the reaction mixture was quenched by saturatedNH₄Cl (100 mL) and separated, the aqueous layer was extracted with DCM(40 mL). The combined organic layers were washed with brine (20 mL),dried over Na₂SO₄, filtered and concentrated under vacuum to givetert-butyl(3aR)-1-oxo-3a,4,6,7-tetrahydro-3H-oxathiazolo[3,4-a]pyrazine-5-carboxylate(5.8 g, 22.1 mmol, 95.6% yield) as a brown solid.

Step B: Tert-butyl(3aR)-1,1-dioxo-3a,4,6,7-tetrahydro-3H-oxathiazolo[3,4-a]pyrazine-5-carboxylate

To a solution of tert-butyl(3aR)-1-oxo-3a,4,6,7-tetrahydro-3H-oxathiazolo[3,4-a]pyrazine-5-carboxylate(7.5 g, 28.6 mmol) in MeCN (225 mL) was added NaIO₄ (7.95 g, 37.2 mmol,2.06 mL) in water (75 mL) followed by RuCl₃.H₂O (129 mg, 572 umol) at 0°C. The reaction mixture was stirred at 15° C. for 0.5 hour. Uponcompletion, the reaction mixture was quenched with saturated NH₄Cl (10mL) and extracted with EtOAc (20 mL). The organic layer was washed withbrine (10 mL), dried over Na₂SO₄, filtered and concentrated undervacuum. The residue was purified by silica gel chromatography(PE:EtOAc=3:1 to 1:1) to give tert-butyl(3aR)-1,1-dioxo-3a,4,6,7-tetrahydro-3H-oxathiazolo[3,4-a]pyrazine-5-carboxylate(7 g, 25.2 mmol, 88.0% yield) as a white solid. ¹H NMR (400 MHz,CHLOROFORM-d) 6=4.64 (dd, J=6.4, 8.0 Hz, 1H), 4.36-3.94 (m, 3H), 3.64(ddt, J=3.6, 6.0, 9.2 Hz, 1H), 3.46 (br d, J=11.6 Hz, 1H), 3.13 (br s,1H), 2.96 (dt, J=3.2, 11.2 Hz, 2H), 1.48 (s, 9H)

Step C: Tert-butyl (3S)-3-(cyanomethyl)piperazine-1-carboxylate

To a solution of tert-butyl(3aR)-1,1-dioxo-3a,4,6,7-tetrahydro-3H-oxathiazolo[3,4-a]pyrazine-5-carboxylate(5 g, 18.0 mmol) in DMF (100 mL) was added KCN (1.04 g, 16.0 mmol,684.94 uL). The reaction mixture was heated to 50° C. for 16 hours. Uponcompletion, the reaction mixture was quenched by HCl (2 M, 50 mL) andstirred at 15° C. for 1 h. The mixture was basidified by NaOH (40%, 10mL) and extracted with EtOAc (3×100 mL). The organic layer was driedover Na₂SO₄ and concentrated under vacuum. The residue was purified bysilica gel chromatography (PE: EtOAc=3:1 to 0:1 then EtOAc: MeOH=100:1to 10:1) to give tert-butyl (3S)-3-(cyanomethyl)piperazine-1-carboxylate(1.1 g, 4.88 mmol, 27.2% yield) as a brown oil. ¹H NMR (400 MHz,CHLOROFORM-d) δ=4.05-3.71 (m, 2H), 3.08-2.88 (m, 3H), 2.84-2.62 (m, 2H),2.56-2.37 (m, 2H), 1.47 (s, 9H).

Step D: 2-[(2S)-piperazin-2-yl]acetonitrile

A reaction mixture of tert-butyl(3S)-3-(cyanomethyl)piperazine-1-carboxylate (850 mg, 3.77 mmol) andHCl/dioxane (4 M, 20 mL) was stirred at 15° C. for 1 hour. Uponcompletion, the solvent was removed under vacuum to give2-[(2S)-piperazin-2-yl]acetonitrile (740 mg, 3.74 mmol, 99.0% yield,2HCl) as a white solid. ¹H NMR (400 MHz, METHANOL-d₄) δ=4.04-3.90 (m,1H), 3.81-3.70 (m, 2H), 3.69-3.61 (m, 2H), 3.53-3.36 (m, 2H), 3.13 (d,J=6.4 Hz, 2H).

Step E:2-[(2S)-4-(7-benzyl-2-chloro-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl]acetonitrile

To a mixture of7-benzyl-2,4-dichloro-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine (1.3 g,4.42 mmol) and 2-[(2S)-piperazin-2-yl]acetonitrile (1.17 g, 5.91 mmol,2HCl) in dioxane (25 mL) was added DIEA (2.86 g, 22.1 mmol, 3.85 mL).The reaction mixture was stirred at 50° C. for 12 hours. Uponcompletion, the reaction mixture was diluted with water (50 mL) andextracted with EtOAc (3×80 mL). The combined organic layers were washedwith brine (30 mL), dried over Na₂SO₄ and concentrated under vacuum togive2-[(2S)-4-(7-benzyl-2-chloro-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl]acetonitrile(1.69 g, 4.41 mmol, 100% yield) as a brown solid.

Step F: Tert-butyl(2S)-4-(7-benzyl-2-chloro-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate

A reaction mixture of2-[(2S)-4-(7-benzyl-2-chloro-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl]acetonitrile(1.69 g, 4.41 mmol) and (Boc)₂O (10.3 g, 47.2 mmol, 10.8 mL) was heatedto 50° C. for 2 hours. Upon completion, the reaction mixture waspurified by silica gel chromatography (PE:EtOAc=10:1 to 1:1) to givetert-butyl(2S)-4-(7-benzyl-2-chloro-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate(1.1 g, 2.12 mmol, 48.0% yield, 93% purity) as brown solid. ES+APCI MSm/z 483.4 [M+H]⁺.

Step G: Tert-butyl(2S)-4-[7-benzyl-2-[2-(dimethylamino)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(cyanomethyl)piperazine-1-carboxylate

To a solution of 2-(dimethylamino)ethanol (415 mg, 4.66 mmol, 468 uL) inTHE (20 mL) was added NaH (149 mg, 3.73 mmol, 60% purity) 0° C. Thereaction mixture was stirred at 0° C. for 0.5 h. To the mixture wasadded tert-butyl(2S)-4-(7-benzyl-2-chloro-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate(900 mg, 1.86 mmol). The reaction mixture was stirred at 70° C. for 12hours at sealed tube under N₂.Upon completion, the reaction mixture wasquenched by water (10 mL) and extracted with EtOAc (3×40 mL). Thecombined organic layers were treated with activated carbon and filtered.The filtrate was concentrated under vacuum to give tert-butyl(2S)-4-[7-benzyl-2-[2-(dimethylamino)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(cyanomethyl)piperazine-1-carboxylate(600 mg, 1.12 mmol, 60.1% yield) as a brown solid.

Step H: tert-butyl(2S)-2-(cyanomethyl)-4-[2-[2-(dimethylamino)ethoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate

NH₃ was bubbled into MeOH (20 mL) for 5 min. To the solution was addedtert-butyl(2S)-4-[7-benzyl-2-[2-(dimethylamino)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(cyanomethyl)piperazine-1-carboxylate(600 mg, 1.12 mmol) and 10% Pd/C (200 mg). The suspension was degassedunder vacuum and purged with H₂ several times. The mixture was stirredunder H₂ (15 psi) at 40° C. for 16 hours. Upon completion, the mixturewas filtered and the filter cake was washed with MeOH (3×30 mL). Thefiltrate was concentrated under vacuum. The residue was purified byprep-HPLC (column: Phenomenex luna(2) C18 250*50 10u; mobile phase:[water (0.225% Formic Acid)-ACN]; B %: %-%, 30 MIN; 60% min) to givetert-butyl(2S)-2-(cyanomethyl)-4-[2-[2-(dimethylamino)ethoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(167 mg, 331 umol, 29.6% yield, 88.3% purity) as a colorless oil.ES+APCI MS m/z 446.3 [M+H]⁺.

Step I: tert-butyl(2S)-2-(cyanomethyl)-4-[2-[2-(dimethylamino)ethoxy]-7-[3-(2,2-dimethylpropanoyloxy)-1-naphthyl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate

To a solution of tert-butyl(2S)-2-(cyanomethyl)-4-[2-[2-(dimethylamino)ethoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(180 mg, 404 umol), (4-bromo-2-naphthyl) 2,2-dimethylpropanoate (248 mg,808 umol) and Cs₂CO₃ (395 mg, 1.21 mmol) in toluene (6 mL) was addedXPHOS Palladacycle Gen 3 (34.20 mg, 40.4 umol). The reaction mixture wasstirred at 70° C. for 4 hours under N₂. Upon completion, the reactionmixture was purified by silica gel chromatography (PE:EA=5:1 to 0:1) togive tert-butyl(2S)-2-(cyanomethyl)-4-[2-[2-(dimethylamino)ethoxy]-7-[3-(2,2-dimethylpropanoyloxy)-1-naphthyl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(200 mg, 272 umol, 67.3% yield, 91.3% purity) as a brown solid. ES+APCIMS m/z 672.0 [M+H]⁺.

Step J:[4-[4-[(3S)-3-(cyanomethyl)piperazin-1-yl]-2-[2-(dimethylamino)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl]-2-naphthyl]2,2-dimethylpropanoate

To a solution of tert-butyl(2S)-2-(cyanomethyl)-4-[2-[2-(dimethylamino)ethoxy]-7-[3-(2,2-dimethylpropanoyloxy)-1-naphthyl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(200 mg, 298 umol) in DCM (0.3 mL) was added TFA (420 mg, 3.68 mmol, 273uL). The reaction mixture was stirred at 15° C. for 1 hour. Uponcompletion, the reaction mixture was concentrated under vacuum to give[4-[4-[(3S)-3-(cyanomethyl)piperazin-1-yl]-2-[2-(dimethylamino)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl]-2-naphthyl]2,2-dimethylpropanoate (238 mg, 298 umol, 99.9% yield, 2TFA) as a brownoil.

Step K:[4-[4-[(3S)-3-(cyanomethyl)-4-prop-2-enoyl-piperazin-1-yl]-2-[2-(dimethylamino)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl]-2-naphthyl]2,2-dimethylpropanoate

To a solution of[4-[4-[(3S)-3-(cyanomethyl)piperazin-1-yl]-2-[2-(dimethylamino)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl]-2-naphthyl]2,2-dimethylpropanoate (238 mg, 298 umol, 2TFA) and DIEA (308 mg, 2.38mmol, 415 uL) in DCM (5 mL) was added prop-2-enoyl prop-2-enoate (56.3mg, 446 umol) at 0° C. The reaction mixture was stirred at 15° C. for 1hour. Upon completion, the reaction mixture was quenched with a drop ofwater. The mixture (was purified by silica gel chromatography(PE:EtOAc=1:1 to 0:1 then EtOAc: MeOH=50:1 to 3:1) to give[4-[4-[(3S)-3-(cyanomethyl)-4-prop-2-enoyl-piperazin-1-yl]-2-[2-(dimethylamino)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl]-2-naphthyl]2,2-dimethylpropanoate (300 mg, crude) as a brown oil. ES+APCI MS m/z626.4 [M+H]⁺.

Step L:2-[(2S)-4-[2-[2-(dimethylamino)ethoxy]-7-(3-hydroxy-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile

To a solution of[4-[4-[(3S)-3-(cyanomethyl)-4-prop-2-enoyl-piperazin-1-yl]-2-[2-(dimethylamino)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl]-2-naphthyl]2,2-dimethylpropanoate (300 mg, 479 umol) in THE (3 mL) was added NaOH(2 M, 3 mL) in water. The reaction mixture was stirred at 15° C. for 8hours. Upon completion, the reaction mixture was acidified by 0.5 mL offormic acid (20% in water) to PH=7 and extracted with DCM (5×10 mL). Thecombined organic layers were dried over Na₂SO₄, filtered andconcentrated under vacuum.

The residue was purified by prep-HPLC (column: Boston Green ODS 150*305u; mobile phase: [water (0.225% Formic Acid)-ACN]; B %: 25%-49%, 10min) to give2-[(2S)-4-[2-[2-(dimethylamino)ethoxy]-7-(3-hydroxy-1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile(18.3 mg, 30.2 umol, two steps 10.1% yield, 96.7% purity, Formic AcidSalt) as a yellow solid. ES+APCI MS m/z 542.5 [M+H]⁺.

Example 1772-[4-[2-[[(3R)-1-methylpyrrolidin-3-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile

Step A: tert-butyl2-(cyanomethyl)-4-[2-[[(3R)-1-methylpyrrolidin-3-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate:To a solution of tert-butyl2-(cyanomethyl)-4-[2-methylsulfinyl-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(300 mg, 549 umol) and [(3R)-1-methylpyrrolidin-3-yl]methanol (126 mg,1.10 mmol) in toluene (6 mL) was added t-BuONa (79.1 mg, 823 umol) at18° C. and the reaction mixture stirred at 18° C. for 0.5 hour. To themixture was then added EtOAc (20 mL) and water (15 mL), then extractedwith EtOAc (3×20 mL). The combined organic layers were washed with brine(20 mL). The combined organic layers were dried over anhydrous Na₂SO₄,filtered and concentrated under reduced pressure. The residue waspurified by reversed phase flash column (ACN/Water (0.1% FormicAcid)=42%) to give tert-butyl2-(cyanomethyl)-4-[2-[[(3R)-1-methylpyrrolidin-3-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(200 mg, 331 umol, 60.4% yield, 99.0% purity) as yellow solid. ES+APCIMS m/z 598.3[M+H]⁺.

Step B:2-[4-[2-[[(3R)-1-methylpyrrolidin-3-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile:A mixture of tert-butyl2-(cyanomethyl)-4-[2-[[(3R)-1-methylpyrrolidin-3-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(200 mg, 334 umol) and TFA (763 mg, 6.69 mmol, 495 uL) was stirred at18° C. for 1 hour. The reaction mixture was concentrated under vacuum togive2-[4-[2-[[(3R)-1-methylpyrrolidin-3-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(250 mg, crude, 2TFA) as brown oil.

Step C:2-[4-[2-[[(3R)-1-methylpyrrolidin-3-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile:To a solution of2-[4-[2-[[(3R)-1-methylpyrrolidin-3-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(250 mg, 344 umol, 2TFA) and DIEA (356 mg, 2.76 mmol, 480 uL) in DCM (5mL) was added prop-2-enoyl prop-2-enoate (65.2 mg, 517 umol) at 0° C.and the mixture was stirred at 18° C. for 1.5 hours. The reactionmixture was quenched with water (3 mL) and then extracted with DCM (3×6mL). The combined organic layers were dried over anhydrous Na₂SO₄,filtered and concentrated under reduced pressure. The residue waspurified by prep-HPLC (column: Phenomenex Gemini 150*25 mm*10 um; mobilephase: [water (10 mM NH₄HCO3)-ACN]; B %: 30%-60%, 3 min) to give2-[4-[2-[[(3R)-1-methylpyrrolidin-3-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile(9.98 mg, 17.0 umol, 4.94% yield, 94.1% purity) as white solid. ES+APCIMS m/z 552.5[M+H]⁺.

Example 1782-[4-[7-(3-hydroxy-1-naphthyl)-2-[[(2R)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile

Step A:7-benzyl-2-methylsulfanyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-ol

A suspension of MeOH (1000 mL) and Na (22.0 g, 957 mmol, 22.7 mL) wasstirred for 30 min. To this mixture was added ethyl1-benzyl-3-oxo-piperidine-4-carboxylate (50 g, 191 mmol and2-methylisothiourea (47.9 g, 344 mmol, 0.5H₂SO₄) at 15° C. The reactionmixture was stirred at 15° C. for 30 hours. The reaction mixture wasacidified by HCl (2 M) (300 mL) until pH=6 and concentrated underreduced pressure. The residue was suspended in 200 mL of water andstirred rapidly. The suspension was filtered and the white solidcollected and washed with ethyl acetate.7-benzyl-2-methylsulfanyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-01 (68g, 151 mmol, 79.1% yield, 64.0% purity) was obtained as a white solid.

Step B:7-benzyl-4-chloro-2-methylsulfanyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine

To a solution of7-benzyl-2-methylsulfanyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-o (50g, 174 mmol) in CHCl₃ (1000 mL) was added POCl₃ (166 g, 1.08 mol, 100mL) and the mixture stirred at 80° C. for 13 hours. Upon completion, thereaction mixture was concentrated under vacuum. The residue was dilutedwith EtOAc (500 mL) and basified using saturated Na₂CO₃ (800 mL) toPH=7. The mixture was extracted with ethyl acetate (3×400 mL). Thecombined organic layers were dried over anhydrous Na₂SO₄, filtered andconcentrated under reduced pressure. The residue was purified by silicagel chromatography (PE: EA from 100:1 to 80:1) to give7-benzyl-4-chloro-2-methylsulfanyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine(21.7 g, 67.4 mmol, 38.7% yield, 95.0% purity) as brown oil. ES+APCI MSm/z 306.1[M+H]⁺.

Step C: tert-butyl4-(7-benzyl-2-methylsulfanyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate

To a solution of7-benzyl-4-chloro-2-methylsulfanyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine(2.6 g, 8.50 mmol) and 2-piperazin-2-ylacetonitrile (1.68 g, 8.50 mmol,2HCl) in DMSO (52 mL) was added DIEA (5.49 g, 42.5 mmol, 7.40 mL). Themixture was warmed to 80° C. and stirred at 80° C. for 6 hours. To themixture was added (Boc)₂O (18.5 g, 85.0 mmol, 19.5 mL) and the mixturestirred at 80° C. for 1 hour. Water (150 mL) was added and the mixturewas extracted with ethyl acetate (3×200 mL). The combined organic phasewas washed with brine (200 mL), dried with anhydrous Na₂SO₄, filteredand concentrated in vacuum. The residue was purified by silica gelchromatography (PE: EA from 10:1 to 0:1) to give tert-butyl4-(7-benzyl-2-methylsulfanyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate(2.74 g, 5.26 mmol, 61.9% yield, 95.0% purity) as brown solid. ES+APCIMS m/z 495.4[M+H]⁺.

Step D: tert-butyl2-(cyanomethyl)-4-(2-methylsulfanyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate

To a solution of tert-butyl4-(7-benzyl-2-methylsulfanyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate(2.51 g, 5.07 mmol) and DIEA (1.97 g, 15.2 mmol, 2.65 mL) in DCE (50 mL)was added 1-chloroethyl carbonochloridate (1.81 g, 12.7 mmol) at 0° C.,and the mixture stirred at 15° C. for 3 hours. The reaction mixture wasconcentrated under vacuum. The residue was dissolved in MeOH (50 mL) andthe reaction mixture was stirred at 70° C. for 1.5 hours. The mixturewas concentrated under vacuum. The residue was purified by prep-HPLC(column: Phenomenex Synergi Max-RP 250*50 mm*10 um; mobile phase: [water(0.225% FA)-ACN]; B %: 23%-48%, 30; 50% min) to give tert-butyl2-(cyanomethyl)-4-(2-methylsulfanyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(1.13 g, 2.51 mmol, 49.5% yield, 90.0% purity) as pink solid. ES+APCI MSm/z 405.3[M+H]⁺.

Step E: tert-butyl2-(cyanomethyl)-4-[7-[3-(2,2-dimethylpropanoyloxy)-1-naphthyl]-2-methylsulfanyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate

To a solution of tert-butyl2-(cyanomethyl)-4-(2-methylsulfanyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(730 mg, 1.80 mmol), (4-bromo-2-naphthyl) 2,2-dimethylpropanoate (832mg, 2.71 mmol) and Cs₂CO₃ (1.76 g, 5.41 mmol) in toluene (18 mL) wasadded [2-(2-aminophenyl)phenyl]palladium(1+);dicyclohexyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphane-methanesulfonate(153 mg, 180 umol), the suspension was degassed under vacuum and purgedwith N₂ several times. The reaction mixture was stirred at 70° C. for 4hours. Upon completion, water (20 mL) was added to the mixture. Theresulting mixture was extracted with EtOAc (4×20 mL). The combinedorganic layers were washed with brine (40 mL), dried over anhydrousNa₂SO₄, filtered and concentrated under reduced pressure The residue waspurified by silica gel chromatography (PE:EtOAc from 30:1 to 0:1) togive tert-butyl2-(cyanomethyl)-4-[7-[3-(2,2-dimethylpropanoyloxy)-1-naphthyl]-2-methylsulfanyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(740 mg, 1.15 mmol, 63.7% yield, 98.0% purity) as brown solid. ES+APCIMS m/z 631.5[M+H]⁺.

Step F: tert-butyl2-(cyanomethyl)-4-[7-[3-(2,2-dimethylpropanoyloxy)-1-naphthyl]-2-methylsulfinyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-vl]piperazine-1-carboxylate

To a solution of tert-butyl2-(cyanomethyl)-4-[7-[3-(2,2-dimethylpropanoyloxy)-1-naphthyl]-2-methylsulfanyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(100 mg, 158 umol) in DCM (2 mL) was added m-CPBA (32.2 mg, 158 umol,85.0% purity) at 0° C. and the mixture stirred at 0° C. for 1 hours. Thereaction mixture was quenched by saturated Na₂S₂O₃ (4 mL) at 0° C. andseparated, then diluted with water (10 mL) and extracted with ethylacetate (10 mL). The combined organic layers were washed with brine (20mL), dried over anhydrous Na₂SO₄, filtered and concentrated underreduced pressure to give a residue. The residue was purified by silicagel chromatography (PE: EA from 10:1 to 0:1) to give tert-butyl2-(cyanomethyl)-4-[7-[3-(2,2-dimethylpropanoyloxy)-1-naphthyl]-2-methylsulfinyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(90 mg, 125 umol, 79.0% yield, 90.0% purity) as brown solid. ES+APCI MSm/z 647.5[M+H]⁺.

Step G: tert-butyl2-(cyanomethyl)-4-[7-[3-(2,2-dimethylpropanoyloxy)-1-naphthyl]-2-[[(2R)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate

To a solution of tert-butyl2-(cyanomethyl)-4-[7-[3-(2,2-dimethylpropanoyloxy)-1-naphthyl]-2-methylsulfinyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(560 mg, 866 umol), [(2R)-1-methylpyrrolidin-2-yl]methanol (199 mg, 1.73mmol) in toluene (10 mL) was added t-BuONa (125 mg, 1.30 mmol) at 0° C.and the mixture was stirred at 0° C. for 0.5 hour. The mixture waspartitioned between EtOAc (20 mL) and water (15 mL) and separated. Thenthe aqueous layer was extracted with EtOAc (3×20 mL). The combinedorganic layers were washed with brine (20 mL), dried over anhydrousNa₂SO₄, filtered and concentrated under reduced pressure. The residuewas purified by reverse phase flash column to give tert-butyl2-(cyanomethyl)-4-[7-[3-(2,2-dimethylpropanoyloxy)-1-naphthyl]-2-[[(2R)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(340 mg, 481 umol, 55.5% yield, 98.7% purity) as brown oil. ES+APCI MSm/z 698.4[M+H]⁺.

Step H:[4-[4-[3-(cyanomethyl)piperazin-1-yl]-2-[[(2R)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl]-2-naphthyl]2,2-dimethylpropanoate

To a solution of tert-butyl2-(cyanomethyl)-4-[7-[3-(2,2-dimethylpropanoyloxy)-1-naphthyl]-2-[[(2R)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(140 mg, 201 umol) in DCM (0.2 mL) was added TFA (229 mg, 2.01 mmol, 148uL) at 15° C. and the mixture was stirred at 15° C. for 5 hours. Thereaction mixture was concentrated under vacuum to give[4-[4-[3-(cyanomethyl)piperazin-1-yl]-2-[[(2R)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl]-2-naphthyl]2,2-dimethylpropanoate (170 mg, crude, 2TFA) as brown oil.

Step I:[4-[4-[3-(cyanomethyl)-4-prop-2-enoyl-piperazin-1-yl]-2-[[(2R)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl]-2-naphthyl]2,2-dimethylpropanoate

To a solution of[4-[4-[3-(cyanomethyl)piperazin-1-yl]-2-[[(2R)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl]-2-naphthyl]2,2-dimethylpropanoate (170 mg, 206 umol, 2TFA) and DIEA (213 mg, 1.65mmol, 287 uL) in DCM (0.3 mL) was added prop-2-enoyl prop-2-enoate (38.9mg, 309 umol) at 0° C. and this mixture was stirred at 15° C. for 1hour. The reaction mixture was quenched by water (0.5 mL), thenconcentrated under vacuum. The residue (DCM:MeOH=10:1) was purified bysilica gel chromatography (from PE:EtOAc=2:1 to EtOAc:MeOH=0:1) to give[4-[4-[3-(cyanomethyl)-4-prop-2-enoyl-piperazin-1-yl]-2-[[(2R)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl]-2-naphthyl]2,2-dimethylpropanoate(170 mg, 182 umol, 88.7% yield, 70.0% purity) as brown oil. ES+APCI MSm/z 652.6[M+H]⁺.

Step J:2-[4-[7-(3-hydroxy-1-naphthyl)-2-[[(2R)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile

To a solution of[4-[4-[3-(cyanomethyl)-4-prop-2-enoyl-piperazin-1-yl]-2-[[(2R)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl]-2-naphthyl]2,2-dimethylpropanoate(170 mg, 261 umol) in THE (1.5 mL) was added NaOH (2 M, 1.5 mL) and thereaction was stirred at 15° C. for 6 hours. The reaction mixture wasneutralized by HCOOH (20%, 0.1 mL) to PH=7. The resulting mixture wasextracted with DCM (3×5 mL), the combined organic layers were dried overanhydrous Na₂SO₄, filtered and concentrated under reduced pressure togive a residue. The residue was purified by prep-HPLC (column: Luna C18150*25 5u; mobile phase: [water (0.225% Formic Acid)-ACN]; B %:12%-39%,10 min) to give2-[4-[7-(3-hydroxy-1-naphthyl)-2-[[(2R)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile(6.88 mg, 11.6 umol, 4.44% yield, 95.6% purity) as yellow solid. ES+APCIMS m/z 568.5[M+H]⁺.

Example 1792-[4-[7-(3-hydroxy-1-naphthyl)-2-[[(3R)-1-methylpyrrolidin-3-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile

Step A: (3R)-1-methylpyrrolidin-3-yl]methanol

To the solution of tert-butyl(3R)-3-(hydroxymethyl)pyrrolidine-1-carboxylate (1 g, 4.97 mmol) in THF(40 mL) was added LiAlH₄ (377 mg, 9.94 mmol) at 0° C., then the mixturewas warmed to 70° C. and stirred at 70° C. for 4 hours. The reactionmixture was quenched by saturated Na₂SO₄ (3 mL) and filtered, the filtercake was washed with THF (5×20 mL). The combined organic phase wasconcentrated under vacuum to give [(3R)-1-methylpyrrolidin-3-yl]methanol(820 mg, crude) as yellow oil. ¹H NMR (400 MHz, chloroform-d)6=3.66-3.62 (dd, J=4.8, 10.0 Hz, 1H), 3.53-3.49 (dd, J=5.6, 10.0 Hz,1H), 3.35-3.18 (m, 1H), 2.77-2.68 (m, 1H), 2.59-2.53 (m, 1H), 2.52-2.45(m, 1H), 2.40-2.33 (m, 1H), 2.32 (s, 3H), 2.31-2.26 (m, 1H), 2.04-1.93(m, 1H), 1.69-1.59 (m, 1H)

Step B: tert-butyl2-(cyanomethyl)-4-[7-[3-(2,2-dimethylpropanoyloxy)-1-naphthyl]-2-[[(3R)-1-methylpyrrolidin-3-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate

To the solution of tert-butyl2-(cyanomethyl)-4-[7-[3-(2,2-dimethylpropanoyloxy)-1-naphthyl]-2-methylsulfinyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(500 mg, 773 umol) and [(3R)-1-methylpyrrolidin-3-yl]methanol (178 mg,1.55 mmol) in toluene (10 mL) was added t-BuONa (111 mg, 1.16 mmol) andthis mixture stirred at 15° C. for 0.5 hour. To the mixture was addedethyl acetate (20 mL) and water (15 mL), then extracted with ethylacetate (3×20 mL). The combined organic layers were washed with brine(20 mL). The combined organic layers were dried over anhydrous Na₂SO₄,filtered and concentrated under reduced pressure. The residue waspurified by reversed phase flash column (ACN/Water (0.1% FormicAcid)=42%) to give tert-butyl2-(cyanomethyl)-4-[7-[3-(2,2-dimethylpropanoyloxy)-1-naphthyl]-2-[[(3R)-1-methylpyrrolidin-3-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(180 mg, 245 umol, 31.7% yield, 95.0% purity) as brown solid. ES+APCI MSm/z 698.6[M+H]⁺.

Step C:[4-[4-[3-(cyanomethyl)piperazin-1-yl]-2-[[(3R)-1-methylpyrrolidin-3-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl]-2-naphthyl]2,2-dimethylpropanoate

A mixture of tert-butyl2-(cyanomethyl)-4-[7-[3-(2,2-dimethylpropanoyloxy)-1-naphthyl]-2-[[(3R)-1-methylpyrrolidin-3-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(180 mg, 258 umol) and TFA (588 mg, 5.16 mmol, 382 uL) was stirred at20° C. for 1.5 hours. The reaction mixture was concentrated under vacuumto give[4-[4-[3-(cyanomethyl)piperazin-1-yl]-2-[[(3R)-1-methylpyrrolidin-3-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl]-2-naphthyl]2,2-dimethylpropanoate (200 mg, crude, 2TFA) as a brown oil.

Step D:[4-[4-[3-(cyanomethyl)-4-prop-2-enoyl-piperazin-1-yl]-2-[[(3R)-1-methylpyrrolidin-3-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl]-2-naphthyl]2,2-dimethylpropanoate

To the solution of[4-[4-[3-(cyanomethyl)piperazin-1-yl]-2-[[(3R)-1-methylpyrrolidin-3-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl]-2-naphthyl]2,2-dimethylpropanoate (200 mg, 242 umol, 2TFA) and DIEA (470 mg, 3.63mmol, 633 uL) in DCM (0.6 mL) was added prop-2-enoyl prop-2-enoate (30.5mg, 242 umol) at 0° C. and the reaction stirred at 15° C. for 1 hour.The reaction mixture was concentrated under vacuum. The residue waspurified by silica gel chromatography (PE:EA=2:1-0:1 to DCM:MeOH=50:11:1) to give[4-[4-[3-(cyanomethyl)-4-prop-2-enoyl-piperazin-1-yl]-2-[[(3R)-1-methylpyrrolidin-3-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl]-2-naphthyl]2,2-dimethylpropanoate (630 mg, crude) as brown oil. ES+APCI MS m/z652.6[M+H]⁺.

Step E:2-[4-[7-(3-hydroxy-1-naphthyl)-2-[[(3R)-1-methylpyrrolidin-3-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile

To a solution of[4-[4-[3-(cyanomethyl)-4-prop-2-enoyl-piperazin-1-yl]-2-[[(3R)-1-methylpyrrolidin-3-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl]-2-naphthyl]2,2-dimethylpropanoate (630 mg, 966 umol) in THE (3 mL) was added NaOH(2 M, 3 mL) at 18° C. and the mixture stirred at 18° C. for 2 hours. Thereaction mixture was neutralized by HCOOH (20%, 0.5 mL) to PH=7. Theresulting mixture was extracted with DCM (3×5 mL), the combined organiclayers were dried over anhydrous Na₂SO₄, filtered and concentrated underreduced pressure. The residue was purified by prep-HPLC (column:Phenomenex Gemini 150*25 mm*10 um; mobile phase: [water (10 mMNH₄HCO3)-ACN]; B %: 35%-65%, 3 min) to give2-[4-[7-(3-hydroxy-1-naphthyl)-2-[[(3R)-1-methylpyrrolidin-3-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile(9.4 mg, 15.8 umol, 1.64% yield, 95.5% purity) as yellow solid. ES+APCIMS m/z 568.5[M+H]⁺.

Example 1804-(3-(4-(piperazin-1-yl)-7-(5-(trifluoromethyl)-1H-indazol-4-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yloxy)propyl)morpholine

Step A.2-[[4-bromo-5-(trifluoromethyl)indazol-1-yl]methoxy]ethyl-trimethyl-silane

To a solution of 4-bromo-5-(trifluoromethyl)-1H-indazole (650 mg, 2.45mmol, 1 eq) in DMF (30 mL) was added NaH (117.71 mg, 2.94 mmol, 60%purity, 1.2 eq) at 0° C. After being stirred at 0° C. for 1 hour, asolution of 2-(chloromethoxy)ethyltrimethyl-silane (531.56 mg, 3.19mmol, 564.29 uL, 1.3 eq) in DMF (10 mL) was added dropwise. The mixturewas warmed to 15° C. and stirred for 2 hours. The mixture was quenchedwith saturated aqueous ammonium chloride solution (50.0 mL), dilutedwith water (100.0 mL) and then extracted with ethyl acetate (3×100.0mL). The organic layer was dried over Na₂SO₄, filtered and concentratedunder vacuum to give a residue. The residue was purified by columnchromatography (SiO₂, Petroleum ether/Ethyl acetate=10:1).2-[[4-bromo-5-(trifluoromethyl)indazol-1-yl]methoxy]ethyl-trimethyl-silane(680 mg, 1.70 mmol, 69.44% yield, 99.0% purity) was obtained as acolorless oil. ES+APCI MS m/z 395.0[M+H]⁺.

Step B. tert-butyl4-[2-(3-morpholinopropoxy)-7-[5-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)indazol-4-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate

A mixture of2-[[4-bromo-5-(trifluoromethyl)indazol-1-yl]methoxy]ethyl-trimethyl-silane(444.35 mg, 1.12 mmol, 1.3 eq), tert-butyl4-[2-(3-morpholinopropoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(400 mg, 864.71 umol, 1 eq), RuPhos (80.70 mg, 172.94 umol, 0.2 eq),Pd₂(dba)₃ (118.77 mg, 129.71 umol, 0.15 eq), and Cs₂CO₃ (845.21 mg, 2.59mmol, 3 eq) in toluene (40 mL) was degassed and purged with N₂ 3 times,and the mixture was stirred at 90° C. for 12 hrs under nitrogen. Thereaction mixture was concentrated under reduced pressure to removetoluene. The residue was diluted with water 100 mL and extracted withEthyl acetate 300 mL (100 mL×3). The combined organic layers were washedwith water 300 mL (100 mL×3), dried over Na₂SO₄, filtered andconcentrated under reduced pressure to give a residue. The residue waspurified by column chromatography (SiO₂, DCM: CH30H=30:1 to 20:1).tert-butyl4-[2-(3-morpholinopropoxy)-7-[5-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)indazol-4-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(400 mg, 446.87 umol, 51.68% yield, 86.8% purity) was obtained as ayellow solid. ES+APCI MS m/z 773.3[M+H]⁺.

Step C.4-[3-[[4-piperazin-1-yl-7-[5-(trifluoromethyl)-1H-indazol-4-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-2-yl]oxy]propyl]morpholine

To a solution oftert-butyl-4-[2-(3-morpholinopropoxy)-7-[5-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)indazol-4-yl]-6,8-dihydro-5Hpyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate (100 mg, 111.72umol, 1 eq) in DCM (2 mL) was added TFA (254.77 mg, 2.23 mmol, 165.43uL, 20 eq) at 25° C. The reaction mixture was stirred at 25° C. for 12hours. The reaction mixture was concentrated in vacuum.4-[3-[[4-piperazin-1-yl-7-[5-(trifluoromethyl)-1H-indazol-4-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-2-yl]oxy]propyl]morpholine(200 mg, crude, TFA) was obtained as a brown color oil. The crudeproduct was used directly to the next step without further purification.ES+APCI MS m/z 547.5[M+H]⁺.

Step D.1-[4-[2-(3-morpholinopropoxy)-7-[5-(trifluoromethyl)-1H-indazol-4-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one

To a solution of4-[3-[[4-piperazin-1-yl-7-[5-(trifluoromethyl)-1H-indazol-4-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-2-yl]oxy]propyl]morpholine(200 mg, TFA) and DIEA (600 mg, 4.64 mmol, 808.63 uL) in DCM (2 mL) wasadded dropwise prop-2-enoyl prop-2-enoate (13 mg, 103.08 umol) at −50°C. The mixture was stirred at −50° C. for 30 min. The mixture wasquenched with water and extracted with ethyl acetate (50 mL), theorganic layer was washed with water (1×20 mL) and brine (1×20 mL). Theseparated organic layer was dried over sodium sulfate, filtered andconcentrated under vacuum. The residue was purified by prep-HPLC (FAcondition) column: Luna C18 150*25 5u; mobile phase: [water (0.225%FA)-ACN]; B %: 15%-36%, 10 min].1-[4-[2-(3-morpholinopropoxy)-7-[5-(trifluoromethyl)-1H-indazol-4-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one(18.26 mg, 28.12 mmol, two steps 23%, 99.6% purity, FA) was obtained asa yellow solid. ES+APCI MS m/z 601.4[M+H]⁺.

Example 1811-(4-(2-(3-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)propoxy)-7-(5-methyl-1H-indazol-4-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Step A. benzyl4-(2-(3-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)propoxy)-7-(5-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-4-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate:To a solution of 3-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)propan-1-ol (107 mg, 681 umol) in THF (2 mL) was addedt-BuONa (98.1 mg, 1.02 mmol) followed by benzyl4-[2-methylsulfinyl-7-[5-methyl-1-(2-trimethylsilylethoxymethyl)indazol-4-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(230 mg, 340 umol). The mixture was stirred at 0° C. for 1 hour. Themixture was poured into water (10 mL) and extracted with DCM (2×10 mL).The organic layer was dried over Na₂SO₄, filtered and concentrated. Theobtained product was purified by prep-HPLC (column: Phenomenex SynergiC18 150*25*10 um; mobile phase: [water (0.1% TFA)-ACN]; B %: 25%-55%, 12min) to give benzyl4-(2-(3-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)propoxy)-7-(5-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-4-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(110 mg, 143 umol, 42.0% yield) was obtained as yellow solid. ¹H NMR(400 MHz, Chloroform-d) δ 8.08-8.01 (m, 1H), 7.45-7.43 (m, 4H),7.37-7.31 (m, 3H), 5.76 (s, 2H), 5.24 (s, 2H), 4.76-4.63 (m, 1H),4.60-4.45 (m, 3H), 4.42 (s, 2H), 4.36-4.24 (m, 1H), 3.96-3.83 (m, 2H),3.79-3.65 (m, 8H), 3.64-3.53 (m, 6H), 3.12-2.92 (m, 1H), 2.90-2.77 (m,2H), 2.48 (s, 3H), 2.44-2.41 (m, 1H), 2.36-2.12 (m, 3H), 0.98-0.93 (m,2H), 0.01-0.03 (m, 9H)

Step B. tert-butyl4-(2-(3-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)propoxy)-7-(5-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-4-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate:To a solution of benzyl 4-(2-(3-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)propoxy)-7-(5-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-4-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(90 mg, 117 umol) and BOC₂O (51.1 mg, 234.1 umol, 53.8 uL) in MeOH (2mL) was added Pd/C (10%, 50 mg) under an N₂ atmosphere. The suspensionwas degassed under vacuum and purged with H₂ several times. The mixturewas stirred under H₂ (15 psi) at 40° C. for 12 hours. The mixture wasfiltered and concentrated. The residue was purified by prep-TLC (SiO₂,DCM/MeOH=10:1) to give tert-butyl4-(2-(3-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)propoxy)-7-(5-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-4-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(30 mg, 40.8 umol). ES+APCI MS m/z 735.6[M+H]⁺.

Step C.(1S,4S)-5-(3-((7-(5-methyl-1H-indazol-4-yl)-4-(piperazin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)oxy)propyl)-2-oxa-5-azabicyclo[2.2.1]heptane:To a solution of tert-butyl 4-(2-(3-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)propoxy)-7-(5-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-4-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(30 mg, 40.8 umol) in DCM (0.5 mL) was added TFA (770 mg, 6.75 mmol)dropwise. The mixture was stirred at 15° C. for 2 hours. The mixture wasconcentrated under vacuum to give(1S,4S)-5-(3-((7-(5-methyl-1H-indazol-4-yl)-4-(piperazin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)oxy)propyl)-2-oxa-5-azabicyclo[2.2.1]heptane(30 mg, crude). ES+APCI MS m/z 505.5[M+H]⁺.

Step D.1-(4-(2-(3-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)propoxy)-7-(5-methyl-1H-indazol-4-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one:To a solution of(1S,4S)-5-(3-((7-(5-methyl-1H-indazol-4-yl)-4-(piperazin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)oxy)propyl)-2-oxa-5-azabicyclo[2.2.1]heptane(20 mg, 39.6 umol, 1 eq) and DIEA (30.7 mg, 238 umol, 41.4 uL, 6 eq) inDCM (2 mL) was added prop-2-enoyl prop-2-enoate (4.00 mg, 31.7 umol, 0.8eq) at −50° C. The mixture was stirred at −40-−20° C. for 0.5 hour. Themixture was concentrated under vacuum. The obtained product was purifiedby prep-HPLC (column: Phenomenex Gemini 150*25 mm*10 um; mobile phase:[water (0.05% ammonia hydroxide v/v)-ACN]; B %: 35%-65%, 12 min). Theproduct1-(4-(2-(3-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)propoxy)-7-(5-methyl-1H-indazol-4-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one(6.48 mg, 11.2 umol, two steps 28.3% yield, 96.8% purity) was obtainedas white solid. ES+APCI MS m/z 559.5[M+H]⁺.

Example 1822-[4-[7-(3-hydroxy-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile

Step A: tert-butyl2-(cyanomethyl)-4-[7-[3-(2,2-dimethylpropanoyloxy)-1-naphthyl]-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate.To a mixture of tert-butyl2-(cyanomethyl)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(190 mg, 403 umol), (4-bromo-2-naphthyl) 2,2-dimethylpropanoate (248 mg,806 umol) and Cs₂CO₃ (394 mg, 1.21 mmol) in toluene (5 mL) was addedXPHOS Palladacycle Gen 3 (34.1 mg, 40.29 umol) and the reaction mixturestirred at 70° C. for 4 hours under N₂. Upon completion, the reactionmixture was purified by silica gel chromatography (PE: EA=3:1 to 0:1) togive tert-butyl2-(cyanomethyl)-4-[7-[3-(2,2-dimethylpropanoyloxy)-1-naphthyl]-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(95 mg, 118 umol). ES+APCI MS m/z 698.4 [M+H]⁺.

Step B:[4-[4-[3-(cyanomethyl)piperazin-1-yl]-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl]-2-naphthyl]2,2-dimethylpropanoate. To a solution of tert-butyl2-(cyanomethyl)-4-[7-[3-(2,2-dimethylpropanoyloxy)-1-naphthyl]-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(40 mg, 57.3 umol) in DCM (0.1 mL) was added TFA (154 mg, 1.35 mmol) at15° C. The reaction mixture was stirred at 15° C. for 1 hour. Uponcompletion, the solvent was removed under vacuum to give[4-[4-[3-(cyanomethyl)piperazin-1-yl]-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl]-2-naphthyl]2,2-dimethylpropanoate(47 mg, 56.9 umol).

Step C:[4-[4-[3-(cyanomethyl)-4-prop-2-enoyl-piperazin-1-yl]-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl]-2-naphthyl]2,2-dimethylpropanoate. To a solution of[4-[4-[3-(cyanomethyl)piperazin-1-yl]-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl]-2-naphthyl]2,2-dimethylpropanoate (47 mg, 56.9 umol) and DIEA (58.9 mg, 455 umol)in DCM (1 mL) was added prop-2-enoyl prop-2-enoate (10.8 mg, 85.4 umol)at 0° C. The reaction mixture was stirred at 15° C. for 1 hour. Uponcompletion, the reaction mixture was quenched by addition of a drop ofwater. The residue was purified by silica gel chromatography(PE:EtOAc=3:1 to EtOAc:MeOH=3:1) to give[4-[4-[3-(cyanomethyl)-4-prop-2-enoyl-piperazin-1-yl]-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl]-2-naphthyl]2,2-dimethylpropanoate (130 mg, crude). ES+APCI MS m/z 652.5 [M+H]⁺.

Step D:2-[4-[7-(3-hydroxy-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile.To a solution of[4-[4-[3-(cyanomethyl)-4-prop-2-enoyl-piperazin-1-yl]-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl]-2-naphthyl]2,2-dimethylpropanoate (250 mg, 384 umol) in THE (1.5 mL) was added NaOH(2 M, 1.5 mL) in water. The reaction mixture was stirred at 15° C. for 9hours. Upon completion, the reaction mixture was acidified by additionof two drops of formic acid (20% in water) to reach a pH=7 and theaqueous layer extracted with DCM (5×10 mL). The combined organic layerswere dried over Na₂SO₄, filtered and concentrated under vacuum. Theresidue was purified by prep-HPLC (column: Boston Green ODS 150*30 5u;mobile phase: [water (0.225% FA)-ACN]; B %: 20%-47%, 10 min) to give2-[4-[7-(3-hydroxy-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile(13.1 mg, 21.2 umol). ES+APCI MS m/z 568.5 [M+H]⁺.

Example 1832-[4-[2-[[(2R)-1-methylpyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile

Step A: tert-butyl2-(cyanomethyl)-4-[2-[[(2R)-1-methylpyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate.To a solution of tert-butyl2-(cyanomethyl)-4-[2-methylsulfinyl-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(300 mg, 549 umol) and [(2S)-1-methylpyrrolidin-2-yl]methanol (126 mg,1.10 mmol, 130 uL) in toluene (6.00 mL) was added t-BuONa (105 mg, 1.10mmol). The mixture was stirred at 20° C. for 0.25 hour. Upon completion,the mixture was filtered and the filtrate was concentrated. The residuewas purified by silica gel chromatography (EA/MeOH 50/1 to 10/1) to givetert-butyl2-(cyanomethyl)-4-[2-[[(2R)-1-methylpyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(300 mg, 427 umol). ES+APCI MS m/z 598.6 [M+H]⁺.

Step B:2-[4-[2-[[(2R)-1-methylpyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile.To a solution of tert-butyl2-(cyanomethyl)-4-[2-[[(2R)-1-methylpyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(270 mg, 452 umol) in DCM (330 uL) was added TFA (515 mg, 4.52 mmol).The mixture was stirred at 20° C. for 0.5 hour and concentrated undervacuum. Then TFA (334 uL) was added. The mixture was stirred at 20° C.for 1 hour. Upon completion, the mixture was concentrated under vacuumto give2-[4-[2-[[(2R)-1-methylpyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(400 mg, crude). ES+APCI MS m/z 498.4 [M+H]⁺.

Step C:2-[4-[2-[[(2R)-1-methylpyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile.To a solution of2-[4-[2-[[(2R)-1-methylpyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(276 mg, 451 umol) and DIEA (1.46 g, 11.3 mmol) in DCM (4.00 mL) wasadded prop-2-enoyl prop-2-enoate (51.2 mg, 406 umol) dropwise at 0° C.The mixture was stirred at 20° C. for 1 hour. Upon completion, themixture was diluted with water (0.5 mL) and extracted with EtOAc (2×10mL). The combined organic layers were dried over Na₂SO₄ and concentratedunder vacuum. The residue was purified by prep-HPLC (column: PhenomenexGemini 150*25 mm*10 um; mobile phase: [water (0.05% ammonia hydroxidev/v)-ACN]; B %: 55%-85%, 12 min) to give2-[4-[2-[[(2R)-1-methylpyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile(37.1 mg, 66.3 umol). ES+APCI MS m/z 552.4 [M+H]⁺.

Example 1841-[4-[7-(3-hydroxy-1-naphthyl)-2-(3-hydroxypropoxy)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one

1-[4-[7-(3-hydroxy-1-naphthyl)-2-(3-hydroxypropoxy)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-onewas prepared following Example 136 substituting3-[tert-butyl(dimethyl)silyl]oxypropan-1-ol for2-(3-methoxypyrrolidin-1-yl)ethanol in Step B. ES+APCI MS m/z 490.3[M+H]⁺.

Example 1851-(4-(2-(3-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)propoxy)-7-(3-hydroxynaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Step A: 3-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)propan-1-ol

To a vial was added (1R,4R)-2-Oxa-5-azabicyclo[2.2.1]heptane HCl salt(0.250 g, 2.522 mmol), CH3CN (5.04 mL) and 3-Bromo-1-propanol (0.274 mL,3.026 mmol). Then K₂CO₃ (1.05 g, 7.57 mmol) was added and the mixturewas warmed to 50° C. where it stirred for 16 hours. The mixture was thencooled to ambient temperature, diluted with CH₂Cl₂ and filtered and thesolid was washed with CH₂Cl₂. The filtrate was then concentrated and thecrude oil was purified via column chromatography (5% MeOH/DCM with 0.2%NH₄OH) to afford the product as a colorless oil.

Step B:1-(4-(2-(3-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)propoxy)-7-(3-hydroxynaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Synthesized according to the method of Example 127 using the followingprocedure in place of that outlined in Step D. To a vial was added3-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)propan-1-ol (0.171 g,1.09 mmol) and benzyl4-(2-chloro-7-(3-(methoxymethoxy)naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(0.125 g, 0.218 mmol) followed by dioxane (0.435 mL). Then Cs₂CO₃ (0.213g, 0.653 mmol) was added and the mixture was heated to 100° C. for 15hours. The reaction was diluted with CH₂Cl₂, filtered and the residualsolid was washed with CH₂Cl₂. The filtrate was then dried over Na₂SO₄,filtered and concentrated. The crude residue was purified by columnchromatography (4% MeOH/DCM with 0.2% NH₄OH) to afford the product as ayellow foam. ES+APCI MS m/z 571.2 [M+H]⁺.

Example 186 Benzyl4-(7-(3-(methoxymethoxy)naphthalen-1-yl)-2-(3-(morpholinomethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate

Benzyl4-(7-(3-(methoxymethoxy)naphthalen-1-yl)-2-(3-(morpholinomethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate

Synthesized according to the method of Example 127 using the followingprocedure in place of that outlined in Step D. To a solution of benzyl4-(2-chloro-7-(3-(methoxymethoxy)naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(0.150 g, 0.261 mmol) and 3-(4-Morpholinomethyl)-phenylboronic acidpinacol ester hydrochloride (0.266 g, 0.784 mmol) in dioxane (2.61 mL)was added Na₂CO₃ (0.523 mL, 1.0452 mmol, 2.0M Aq). The mixture wasdegassed by argon bubbling for 5 min. ThenTetrakis(triphenylphosphine)palladium (0) (0.030 g, 0.026 mmol) wasadded and the mixture was heated to 95° C. where it stirred for 7 hours.The reaction was cooled to ambient temperature and then diluted withCH2C2 and filtered. The solid was washed with CH2C12. The filtrate wasthen dried over Na₂SO₄, filtered and concentrated. The crude residue waspurified by column chromatography (30-50% EtOAc/DCM) to afford theproduct as a yellow foam. ES+APCI MS m/z 591.3 [M+H]⁺.

Example 187(R)-1-(4-(7-(3-hydroxynaphthalen-1-yl)-2-((1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

(R)-1-(4-(7-(3-hydroxynaphthalen-1-yl)-2-((1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

This compound was prepared following Example 127 substitutingN-Methyl-D-prolinol for N-Methyl-L-prolinol in Step D. ES+APCI MS m/z529.3 [M+H]⁺.

Example 188(S)-1-(4-(7-(3-hydroxynaphthalen-1-yl)-2-((1-methylpyrrolidin-3-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

(S)-1-(4-(7-(3-hydroxynaphthalen-1-yl)-2-((1-methylpyrrolidin-3-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

This compound was prepared following Example 127 substituting(3S)-(1-Methyl-pyrrolidin-3-yl)-methanol for N-Methyl-L-prolinol in StepD. ES+APCI MS m/z 529.2 [M+H]⁺.

Example 189

1-(4-(2-((1-benzylpyrrolidin-3-yl)methoxy)-7-(3-hydroxynaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

1-(4-(2-((1-benzylpyrrolidin-3-yl)methoxy)-7-(3-hydroxynaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

This compound was prepared following Example 127 substituting(1-Benzylpyrrolidin-3-yl)methanol for N-Methyl-L-prolinol in Step D.ES+APCI MS m/z 605.3 [M+H]⁺.

Example 1901-(4-(2-((1-cyclopropylpyrrolidin-3-yl)methoxy)-7-(3-hydroxynaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

1-(4-(2-((1-cyclopropylpyrrolidin-3-yl)methoxy)-7-(3-hydroxynaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

This compound was prepared following Example 127 substituting(1-Cyclopropyl-3-pyrrolidinyl)methanol for N-Methyl-L-prolinol in StepD. ES+APCI MS m/z 555.3 [M+H]⁺.

Example 1911-((2S,6R)-4-(7-(3-hydroxynaphthalen-1-yl)-2-(3-morpholinopropoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2,6-dimethylpiperazin-1-yl)prop-2-en-1-one

Step A: Benzyl4-((3S,5R)-4-(tert-butoxycarbonyl)-3,5-dimethylpiperazin-1-yl)-2-chloro-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate

A suspension of benzyl2,4-dichloro-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate (500mg, 1.48 mmol), tert-butyl cis-2,6-dimethylpiperazine-1-carboxylate (349mg, 1.63 mmol) and DIEA (0.26 mL) in N,N-dimethylacetamide (1 mL) wasstirred at r.t. overnight. The reaction mixture was divided betweenEtOAc (15 mL) and 1M NaHCO₃ (5 mL) and the layers separated. The organiclayer was washed with 2M Na₂CO₃ and brine (2 mL each), dried over Na₂SO₄and evaporated in vacuo. The residue was chromatographed on silica gelRedisep 24 g column using 20 to 50% EtOAc in hexane as eluent to give acolorless solid (0.440 g, 58%). ES+APCI MS m/z 516.2 [M+H]⁺.

Step B: Benzyl4-((3S,5R)-4-(tert-butoxycarbonyl)-3,5-dimethylpiperazin-1-yl)-2-(3-morpholinopropoxy)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate

A mixture of benzyl4-((3S,5R)-4-(tert-butoxycarbonyl)-3,5-dimethylpiperazin-1-yl)-2-chloro-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate(400 mg, 0.775 mmol), 3-morpholinopropan-1-ol (400 mg, 2.33 mmol, 5eq.), cesium carbonate (1.26 g, 3.88 mmol, 5 eq.) and dioxane (3 mL) ina 4-mL vial was purged with nitrogen. The vial was capped and themixture stirred at 110° C. for 20 h, then at 120° C. overnight. Thereaction was cooled, diluted with EtOAc (10 mL), filtered through Celiteand evaporated in vacuo. The product was purified by chromatography onsilica, Redisep 40 g, using 2 to 10% MeOH/DCM+0.2% NH₄OH as eluent togive a light-yellow amorphous solid (272 mg, 56%).

Step C: tert-butyl(2S,6R)-2,6-dimethyl-4-(2-(3-morpholinopropoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate

A mixture of benzyl4-((3S,5R)-4-(tert-butoxycarbonyl)-3,5-dimethylpiperazin-1-yl)-2-(3-morpholinopropoxy)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate(272 mg, 0.095 mmol), palladium on carbon (50 mg, Degussa Type, 10 wt %,50% H₂O), EtOH (5 mL) and THE (5 mL) was purged with hydrogen andstirred under H₂ atmosphere (rubber balloon) for 3 hours. The reactionmixture was diluted with EtOH (3 mL), filtered through Celite and thecelite washed with EtOH (2×2 mL). The combined organics were evaporatedin vacuo and dried under high vacuum over 2 days to give an off-whitefoam (205 mg, 96%). ES+APCI MS m/z 491.3 [M+H]⁺.

Step D: Tert-butyl(2S,6R)-4-(7-(3-(methoxymethoxy)naphthalen-1-yl)-2-(3-morpholinopropoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2,6-dimethylpiperazine-1-carboxylate

To a stirred suspension of tris(dibenzylideneacetone)dipalladium (0) (19mg, 0.020 mmol) in dry degassed toluene (0.5 mL) at room temperatureunder nitrogen was added(+/−)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (24 mg, 0.038 mmol).The mixture was then heated to 100° C. for 15 minutes. The resulted darkmixture was cooled to room temperature and solid sodium-t-butoxide (39mg, 0.41 mmol) was added, followed by a solution of3-(methoxymethoxy)naphthalen-1-yl trifluoromethanesulfonate (82 mg, 0.25mmol) and tert-butyl(2S,6R)-2,6-dimethyl-4-(2-(3-morpholinopropoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(100 mg, 0.20 mmol) in degassed dry toluene (0.5 mL). The flask wasclosed and heated with stirring to 100° C. for 30 min. The reactionmixture was cooled and divided between EtOAc (20 mL) and water (10 mL).The organic layer was separated and washed with brine, dried over Na₂SO₄and evaporated in vacuo. The product was purified by chromatography onsilica, Redisep 40 g, using 4% MeOH+0.1% NH₄OH in DCM as eluent to givea colorless solid (87 mg, 63%). ES+APCI MS m/z 684.3 [M+H]⁺.

Step E:1-((2S,6R)-4-(7-(3-hydroxynaphthalen-1-yl)-2-(3-morpholinopropoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2,6-dimethylpiperazin-1-yl)prop-2-en-1-one

Tert-butyl(2S,6R)-4-(7-(3-(methoxymethoxy)naphthalen-1-yl)-2-(3-morpholinopropoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2,6-dimethylpiperazine-1-carboxylate(87 mg, 0.129 mmol) was dissolved in 1M TFA/DCM. The reaction mixtureturned red-brown, then dark-red. LCMS indicated non-selectivedeprotection of Boc and MOM. After stirring 30 min at room temperature,0.2 mL of additional TFA was added and the reaction mixture was left atroom temperature for another 30 min. The resulted biphasic mixture wasvaporated in vacuo, divided between water (5 mL) and DCM (10 mL)+NEt₃(0.5 mL) and the organic layer separated. The organic layer was driedover Na₂SO₄ and evaporated in vacuo. The residue was purified bychromatography on silica, Redisep 40 g, using 6% MeOH in DCM+0.2% NH₄OHas eluent to give another residue which was repurified on reverse phase,C18, 5-95% MeCN—H₂O+0.1% TFA to give product assumed to be the bis-saltwith TFA (1.35 mg, 1.3%). ES+APCI MS m/z 587.3 [M+H]⁺.

Example 192(R)-1-(4-(7-(3-hydroxynaphthalen-1-yl)-2-((1-methylpiperidin-3-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

(R)-1-(4-(7-(3-hydroxynaphthalen-1-yl)-2-((1-methylpiperidin-3-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

This compound was prepared following Example 127 substituting3-Piperidinemethanol, 1-methyl-(3R)-for N-Methyl-L-prolinol in Step D.ES+APCI MS m/z 543.3 [M+H]⁺.

Example 1931-(4-(7-(3-hydroxynaphthalen-1-yl)-2-((4-methylmorpholin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

1-(4-(7-(3-hydroxynaphthalen-1-yl)-2-((4-methylmorpholin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

This compound was prepared following Example 127 substituting(4-methyl-2-morpholinyl)methanol for N-Methyl-L-prolinol in Step D.ES+APCI MS m/z 545.3 [M+H]⁺.

Example 1941-(4-(7-(3-hydroxynaphthalen-1-yl)-2-((4-methylmorpholin-3-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

1-(4-(7-(3-hydroxynaphthalen-1-yl)-2-((4-methylmorpholin-3-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

This compound was prepared following Example 127 substituting4-Methyl-3-(hydroxymethyl)morpholine for N-Methyl-L-prolinol in Step D.ES+APCI MS m/z 545.2 [M+H]⁺.

Example 195(R)-1-(4-(7-(3-hydroxynaphthalen-1-yl)-2-((1-methylpiperidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

(R)-1-(4-(7-(3-hydroxynaphthalen-1-yl)-2-((1-methylpiperidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

This compound was prepared following Example 127 substituting(R)-(1-Methylpiperidin-2-yl)methanol for N-Methyl-L-prolinol in Step D.ES+APCI MS m/z 543.3 [M+H]⁺.

Example 196(S)-1-(4-(7-(3-hydroxynaphthalen-1-yl)-2-((1-methylpiperidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

(S)-1-(4-(7-(3-hydroxynaphthalen-1-yl)-2-((1-methylpiperidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

This compound was prepared following Example 127 substituting(S)-(1-Methylpiperidin-2-yl)methanol for N-Methyl-L-prolinol in Step D.ES+APCI MS m/z 543.2 [M+H].

Example 197(S)-1-(4-(2-((1-ethylpyrrolidin-2-yl)methoxy)-7-(3-hydroxynaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

(S)-1-(4-(2-((1-ethylpyrrolidin-2-ylmethoxy)-7-(3-hydroxynaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

This compound was prepared following Example 127 substituting[(2S)-1-Ethyl-2-pyrrolidinyl]methanol for N-Methyl-L-prolinol in Step D.ES+APCI MS m/z 543.3 [M+H]⁺.

Example 198(S,E)-1-(4-(7-(3-hydroxynaphthalen-1-yl)-2-((1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)but-2-en-1-one

S,E)-1-(4-(7-(3-hydroxynaphthalen-1-yl)-2-((1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)but-2-en-1-one

This compound was prepared following Example 127 substitutingtrans-Crotonyl chloride for Acryloyl Chloride in Step F. ES+APCI MS m/z543.2[M+H]⁺.

Example 199(S,E)-4-(dimethylamino)-1-(4-(7-(3-hydroxynaphthalen-1-yl)-2-((1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)but-2-en-1-one

(S,E)-4-(dimethylamino)-1-(4-(7-(3-hydroxynaphthalen-1-yl)-2-((1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)but-2-en-1-one

This compound was prepared following Example 127 substituting thefollowing procedure for step F.7-(3-(methoxymethoxy)naphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-4-(piperazin-1-yl)-4a,5,6,7,8,8a-hexahydropyrido[3,4-d]pyrimidine(150 mg, 0.288 mmol) was dissolved in DCM (5 mL) and treated with(2E)-4-(Dimethylamino)but-2-enoic acid (74.4 mg, 0.576 mmol) and Hunig'sbase (252 μl, 1.44 mmol). To this mixture was added EDC (55.2 mg, 0.288mmol) and HOBT (38.9 mg, 0.288 mmol) neat as powders. The reactionmixture was stirred at room temperature for 1 hour and heated to 35° C.for an additional 3 hours. The reaction mixture was concentrated invacuo and purified on the CombiFlash (0%-15% DCM/MeOH w/1% NH₄OHmodifier). All fractions containing clean desired product were combinedand concentrated in vacuo to afford(E)-4-(dimethylamino)-1-(4-(7-(3-(methoxymethoxy)naphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-4a,5,6,7,8,8a-hexahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)but-2-en-1-one(105 mg, 0.166 mmol, 57.7% yield). The product followed the rest ofExample 127 accordingly to give(S,E)-4-(dimethylamino)-1-(4-(7-(3-hydroxynaphthalen-1-yl)-2-((1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)but-2-en-1-one(14.8 mg, 0.025 mmol, 15.2% yield). ES+APCI MS m/z 586.3[M+H]⁺.

Example 200(S)-1-(4-(2-((1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

(S)-1-(4-(2-((1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-y)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

This compound was prepared following Example 127 substitutingnaphthalen-1-yl trifluoromethanesulfonate for3-(methoxymethoxy)naphthalen-1-yl trifluoromethanesulfonate in Step Cand not performing step F. ES+APCI MS m/z 513.3 [M+H]f.

Example 2011-((R)-2-methyl-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

1-((R)-2-methyl-4-(2-(((S)-1-methylpyrrolidin-2-yl]methoxy)-7-(naphthalen-1-yl]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl)prop-2-en-1-one

This compound was prepared following Example 127 substituting (R)-benzyl2-methylpiperazine-1-carboxylate for benzyl piperazine-1-carboxylate inStep A and substituting naphthalen-1-yl trifluoromethanesulfonate for3-(methoxymethoxy)naphthalen-1-yl trifluoromethanesulfonate in Step Cand not performing step F. ES+APCI MS m/z 527.3 [M+H]⁺.

Example 2021-((S)-4-(7-(3-hydroxynaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-3-methylpiperazin-1-yl)prop-2-en-1-one

1-((S)-4-(7-(3-hydroxynaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-3-methylpiperazin-1-yl)prop-2-en-1-one

This compound was prepared following Example 127 substituting benzyl(S)-3-methylpiperazine-1-carboxylate for benzyl piperazine-1-carboxylatein Step A. ES+APCI MS m/z 543.3 [M+H]⁺.

Example 2031-((S)-4-(7-(3-hydroxynaphthalen-1-yl)-2-(((R)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-3-methylpiperazin-1-yl)prop-2-en-1-one

1-((S)-4-(7-(3-hydroxynaphthalen-1-yl)-2-(((R)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-3-methylpiperazin-1-yl)prop-2-en-1-one

This compound was prepared following Example 127 substituting benzyl(S)-3-methylpiperazine-1-carboxylate for benzyl piperazine-1-carboxylatein Step A and substituting N-Methyl-D-prolinol for N-Methyl-L-prolinolin Step D. ES+APCI MS m/z 543.3 [M+H]⁺.

Example 204

1-(4-(2-((1-cyclopropylpiperidin-4-yl)amino)-7-(3-hydroxynaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Step A: Benzyl4-(2-((1-cyclopropylpiperidin-4-yl)amino)-7-(3-(methoxymethoxy)naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate

A mixture of benzyl4-(2-chloro-7-(3-(methoxymethoxy)naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(75 mg, 0.13 mmol), 1-cyclopropylpiperidin-4-amine (55 mg, 0.39 mmol)and dioxane (0.5 mL) was heated to 120° C. for 36 h. The reactionmixture was cooled to room temperature, divided between EtOAc (10 mL)and water (3 mL) and the layers separated. The organic layer was washedwith brine, dried over Na₂SO₄ and evaporated in vacuo and the residuechromatographed on silica, Redisep 24 g, using 6 to 10% MeOH in DCM+0.2%NH₄OH as eluent to give a colorless solid (43 mg, 49%). ES+APCI MS m/z678.3 [M+H]⁺.

Step B:1-(4-(2-((1-cyclopropylpiperidin-4-yl)amino)-7-(3-(methoxymethoxy)naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

A mixture of benzyl4-(2-((1-cyclopropylpiperidin-4-yl)amino)-7-(3-(methoxymethoxy)-naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(43 mg, 0.063 mmol), palladium on carbon (20 mg, Degussa Type, 10 wt %,50% H₂O), EtOH (1.5 mL) and THE (1.5 mL) was purged with hydrogen andstirred under H₂ atmosphere (rubber balloon) for 3 hours. The mixturewas diluted with EtOH (3 mL), filtered through Celite and the celitewashed with EtOH (2×2 mL). The combined organics were evaporated invacuo. The residue was dissolved in DCM (5 mL) and cooled on ice-saltbath with stirring. Triethylamine (0.03 mL) was next added at once,followed by acryloyl chloride (10 μL). After 1 min at −5° C. thereaction was quenched with NH₄OH (0.05 mL) and evaporated in vacuo. Theresidue was stirred 5 min with DCM (5 mL), filtered and chromatographedon silica gel, Redisep 12 g, using 6 to 20% MeOH in DCM+0.2% NH₄OH aseluent to give a colorless solid (22 mg, 48%). ES+APCI MS m/z 598.3[M+H]⁺.

Step C:1-(4-(2-((1-cyclopropylpiperidin-4-yl)amino)-7-(3-hydroxynaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

To a stirred solution of1-(4-(2-((1-cyclopropylpiperidin-4-yl)amino)-7-(3-(methoxymethoxy)naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one(22 mg, 0.037 mmol) in a mixture of MeOH and THE 1:1 (3 mL) was added 6Maqueous HCl (0.3 mL, 34 eq.) all at once and the resulting solution washeated with stirring at 50° C. for 1.5 hours. The reaction mixture wascooled to room temperature, divided between EtOAc (15 mL) and 0.5MNa₂CO₃ (10 mL) and the organic layer separated. The combined organicswere washed with brine (3 mL), dried over Na₂SO₄ and evaporated invacuo. The residue was chromatographed on silica, Redisep 12 g, using 8to 10% MeOH in DCM+0.2% NH₄OH as eluent to give a colorless solid (15mg, 74%). ES+APCI MS m/z 554.3 [M+H]⁺.

Example 2051-(4-(7-(6-hydroxyquinolin-8-yl)-2-(3-morpholinopropoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Step A: Benzyl4-(7-(6-(methoxymethoxy)quinolin-8-yl)-2-(3-morpholinopropoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate

To a stirred suspension of tris(dibenzylideneacetone)dipalladium (0) (17mg, 0.019 mmol) in degassed dry toluene (0.5 mL) under nitrogen at roomtemperature was added (+/−)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl(24 mg, 0.038 mmol) and the mixture was heated to 100° C. for 15minutes. The dark mixture was cooled to room temperature and solidsodium-t-butoxide (36 mg, 0.38 mmol) was then added, followed by asolution of 8-bromo-6-(methoxymethoxy)quinoline (61 mg, 0.23 mmol) andbenzyl4-(2-(3-morpholinopropoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(94 mg, 0.19 mmol) in degassed dry toluene (0.5 mL). The flask wasclosed and heated to 100° C. for 1 hour. The reaction mixture was cooledto room temperature, divided between EtOAc (15 mL) and water (5 mL) andthe organic layers separated. The organic layer was washed with brine,dried over Na₂SO₄ and evaporated in vacuo. The residue waschromatographed on silica gel, Redisep 24 g, using 4 to 10% MeOH indichloromethane (+0.2% NH₄OH) as eluent to give a yellow solid (28 mg,22%). ES+APCI MS m/z 684.3 [M+H]⁺.

Step B:1-(4-(7-(6-(methoxymethoxy)quinolin-8-yl)-2-(3-morpholinopropoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

A mixture of benzyl4-(7-(6-(methoxymethoxy)quinolin-8-yl)-2-(3-morpholinopropoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(28 mg, 0.095 mmol), Pd/C (15 mg, Degussa Type, 10 wt %, 50% H₂O), EtOH(2 mL) and THE (2 mL) was purged with hydrogen and stirred under H₂atmosphere (rubber balloon) for 2 hours. The reaction mixture wasdiluted with EtOH (3 mL), filtered through Celite and the celite washedwith EtOH (2×2 mL) and the combined organics evaporated in vacuo. Theresulted solid was dissolved in DCM (5 mL) and cooled in an ice-saltbath with stirring. Triethylamine (0.04 mL, 3 eq.) was then added atonce followed by acryloyl chloride (16 μL, 2 eq.). After 1 min at −5° C.the reaction was quenched with NH₄OH (0.05 mL) and evaporated in vacuo.The mixture was filtered through a cotton plug, chromatographed onsilica gel, Redisep 12 g, using 6 to 10% MeOH in DCM+0.2% NH₄OH aseluent to give another residue which was repurified on reverse phase,C18, 5 to 95% MeCN, +0.1% HCO₂H to give product which was assumed to bethe bis-formate salt as a yellow solid (12 mg, 42%). ES+APCI MS m/z604.2 [M+H]⁺.

Step C:1-(4-(7-(6-hydroxyquinolin-8-yl)-2-(3-morpholinopropoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

To a stirred solution of1-(4-(7-(6-(methoxymethoxy)quinolin-8-yl)-2-(3-morpholinopropoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one(12 mg, 0.017 mmol) in a mixture of MeOH and THE 1:1 (1 mL) was added 6Maqueous HCl (0.1 mL, 35 eq.) at once and the solution was heated withstirring at 50° C. for 1.5 h. The reaction mixture was cooled to roomtemperature, divided between EtOAc (15 mL) and 0.5M Na-phosphate bufferwith pH 8 (5 mL) and the layers separated. The combined organics werewashed with brine (1 mL), dried over Na₂SO₄ and evaporated in vacuo. Theproduct was purified by chromatography on silica, Redisep 12 g, using 7to 10% MeOH in DCM+0.2% NH₄OH as eluent to give a residue which wasrepurified by reverse phase chromatography, C18, 5 to 95% MeOH+0.1% TFA)to give product as the tris TFA salt as a colorless solid (4.87 mg,31%). ES+APCI MS m/z 560.3 [M+H]⁺.

Example 2061-(4-(2-(3-(3-azabicyclo[3.1.0]hexan-3-yl)propoxy)-7-(3-hydroxynaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Step A: 3-(3-azabicyclo[3.1.0]hexan-3-yl)propan-1-ol

A mixture of 3-azabicyclo[3.1.0]hexane hydrochloride (200 mg, 1.67mmol), 3-bromopropan-1-ol (166 μL, 1.84 mmol, 1.1 eq.), K₂CO₃ (0.69 g,5.02 mmol, 3 eq.), NaI (251 mg, 1.67 mmol, 1 eq.) and acetonitrile (2mL) in a 4-mL vial was flushed with N₂. The vial was capped and stirredat room temperature for 2 days. The mixture was diluted with water (2mL) and extracted with ether (15 mL). The ether solution was washed withbrine, dried over Na₂SO₄ and decanted into a pear-shaped flask andtrifluoroacetic acid (128 μL, 1 eq) added and the mixture wasconcentrated to ˜5 mL. The upper etherial layer was decanted anddiscarded, the residual oily liquid was dried under vacuum overnight.The oily liquid was diluted with water (0.5 mL) then ether (10 mL) wasadded with stirring followed by 50% NaOH (0.2 mL, 2.5 mmol, 2 eq.). Thelayers were separated, the organic solution was dried over KOH andcarefully concentrated under nitrogen to yield crude3-(3-azabicyclo[3.1.0]hexan-3-yl)propan-1-ol as colorless oil. Used onthe next stage without further purification.

Step B: Benzyl4-(2-(3-(3-azabicyclo[3.1.0]hexan-3-yl)propoxy)-7-(3-(methoxymethoxy)-naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate

A mixture of benzyl4-(2-chloro-7-(3-(methoxymethoxy)naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(75 mg, 0.13 mmol), crude 3-(3-azabicyclo[3.1.0]hexan-3-yl)propan-1-ol(55 mg, 0.39 mmol, 3 eq.), Cs₂CO₃ (213 mg, 0.65 mmol, 5 eq.) and dioxane(0.5 mL) in a 1.7-mL vial was purged with nitrogen. The vial was cappedand stirred at 120° C. over the weekend. The reaction mixture wascooled, divided between EtOAc (15 mL) and water (5 mL) and the layersseparated. The organic layer was washed with brine, dried over Na₂SO₄,evaporated in vacuo and the residue chromatographed on silica gel,Redisep 24 g, using 4 to 10% MeOH+1% NH₄OH as eluent to give product.ES+APCI MS m/z 679.3 [M+H]⁺.

Step C:1-(4-(2-(3-(3-azabicyclo[3.1.0]hexan-3-yl)propoxy)-7-(3-(methoxymethoxy)naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

A mixture of benzyl4-(2-(3-(3-azabicyclo[3.1.0]hexan-3-yl)propoxy)-7-(3-(methoxymethoxy)-naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(49 mg, 0.072 mmol), palladium on carbon (12 mg, Degussa Type, 10 wt %,50% H₂O), EtOH (1.5 mL) and THE (1.5 mL) was purged with hydrogen andstirred under H₂ atmosphere (rubber balloon) for 3 hours. The reactionmixture was diluted with EtOH (3 mL), filtered through Celite and thecelite washed with EtOH (2×2 mL). The combined organics were evaporatedin vacuo. The resulted colorless solid was dissolved in DCM (5 mL),cooled in an ice-salt bath with stirring and triethylamine (0.04 mL, 3eq.) was added at once followed by addition of acryloyl chloride (16 μL,2 eq.). After 1 min at −5° C. the reaction was quenched with NH₄OH (0.05mL) and evaporated in vacuo. The crude product was dissolved in DCM (5mL), filtered through a cotton plug and chromatographed on silica gel,Redisep 12 g, using 6 to 10% MeOH in DCM+0.2% NH₄OH as eluent to give acolorless solid (30 mg, 69%). ES+APCI MS m/z 599.3 [M+H]⁺.

Step D:1-(4-(2-(3-(3-azabicyclo[3.1.0]hexan-3-ylpropoxy)-7-(3-hydroxynaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Toa stirred solution of1-(4-(2-(3-(3-azabicyclo[3.1.0]hexan-3-yl)propoxy)-7-(3-(methoxymethoxy)naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one(30 mg, 0.050 mmol) in a mixture of MeOH and THE 1:1 (3 mL) was added 6Maqueous HCl (0.3 mL, 36 eq.) and the solution was heated with stirringat 50° C. for 1.5 h. The reaction mixture was cooled to roomtemperature, divided between EtOAc (20 mL) and 0.5M Na₂CO₃ (5 mL) andthe layers separated. The organic layer was washed with brine (1 mL),dried over Na₂SO₄ and evaporated in vacuo. The residue waschromatographed on silica, Redisep 12 g, using 6% MeOH in DCM+0.2% NH₄OHas eluent to give a colorless solid (20.62 mg, 74%). ES+APCI MS m/z555.4 [M+H]⁺.

Example 207(R)-1-(4-(2-(2-(3-fluoropiperidin-1-yl)ethoxy)-7-(3-hydroxynaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Step A: (R)-2-(3-fluoropiperidin-1-yl)ethan-1-ol

A mixture of R-3-fluoropiperidine hydrochloride (209 mg, 1.50 mmol),2-bromoethan-1-ol (117 μL, 1.65 mmol, 1.1 eq.), K₂CO₃ (0.62 g, 4.5 mmol,3 eq.), sodium iodide (225 mg, 1.5 mmol, 1 eq.) and acetonitrile (2 mL)in a 4-mL vial was flushed with N₂. The vial was capped and stirred atroom temperature for 2 days. The resulted suspension was diluted withwater (2 mL) and extracted with ether (15 mL). The ether solution waswashed with brine, dried over Na₂SO₄ and decanted into a pear-shapedflask and trifluoroacetic acid (115 μL, 1 eq) was added and the mixturewas concentrated to −5 mL. The upper ethereal layer was decanted, theresidual oily liquid was dried under vacuum overnight. The oily liquidwas diluted with water (0.5 mL) and ether (10 mL) with stirring,followed by addition of 50% NaOH (0.2 mL, 2.5 mmol, 2 eq.). The layerswere separated, the organic solution was dried over KOH, filtered andcarefully concentrated under nitrogen to yield crude amino alcohol as acolorless oil (120 mg, 54%).

Step B: Benzyl(R)-4-(2-(2-(3-fluoropiperidin-1-yl)ethoxy)-7-(3-(methoxymethoxy)naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate

A mixture of benzyl4-(2-chloro-7-(3-(methoxymethoxy)naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(75 mg, 0.13 mmol), crude (R)-2-(3-fluoropiperidin-1-yl)ethan-1-ol (58mg, 0.39 mmol), Cs₂CO₃ (213 mg, 0.65 mmol), and dioxane (0.5 mL) in a1.7-mL vial was purged with nitrogen. The vial was capped and stirred at110° C. for 48 hours. The reaction mixture was cooled, diluted withEtOAc (1 mL), filtered through Celite and the celite washed with EtOAc(2×2 mL) and the combined organics evaporated in vacuo. The residue waschromatographed on silica, Redisep 24 g, using 6% MeOH in DCM+0.2% NH₄OHas eluent to give a colorless solid (30 mg, 34%). ES+APCI MS m/z 685.4[M+H]⁺.

Step C:(R)-1-(4-(2-(2-(3-fluoropiperidin-1-yl)ethoxy)-7-(3-(methoxymethoxy)naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

A mixture of benzyl(R)-4-(2-(2-(3-fluoropiperidin-1-yl)ethoxy)-7-(3-(methoxymethoxy)-naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(30 mg, 0.044 mmol), palladium on carbon (10 mg, Degussa Type, 10 wt %,50% H₂O), EtOH (1.5 mL) and THE (1.5 mL) was purged with hydrogen andstirred under H₂ atmosphere (rubber balloon) for 2 hours. The reactionmixture was diluted with EtOH (3 mL), filtered through Celite and thecelite washed with EtOH (2×2 mL). The combined organics were evaporatedin vacuo. The residue was dissolved in DCM (3 mL) and cooled in anice-salt bath with stirring. Triethylamine (0.02 mL, 3 eq.) was nextadded at once followed by addition of acryloyl chloride (7 μL, 2 eq.).After 1 min at −10° C. the reaction was quenched with NH₄OH (0.03 mL)and evaporated in vacuo. The residue was dissolved in DCM (5 mL),filtered, and chromatographed on silica gel, Redisep 12 g, using 6 to10% MeOH in DCM+0.2% NH₄OH in DCM as eluent to give a colorless solid(22 mg, 83%). ES+APCI MS m/z 605.3 [M+H]⁺.

Step D:(R)-1-(4-(2-(2-(3-fluoropiperidin-1-ylethoxy)-7-(3-hydroxynaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

To a stirred solution of(R)-1-(4-(2-(2-(3-fluoropiperidin-1-yl)ethoxy)-7-(3-(methoxymethoxy)naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one(22 mg, 0.036 mmol) in a mixture of MeOH and THE 1:1 (3 mL) was added 6Maqueous HCl (0.3 mL) and the solution was heated with stirring at 50° C.for 1.5 h. The reaction mixture was cooled to room temperature, dividedbetween EtOAc (20 mL) and 0.5M Na₂CO₃ (5 mL) and the layers separated.The organic layer was washed with brine (1 mL), dried over Na₂SO₄ andevaporated in vacuo. The residue was chromatographed on silica gel,Redisep 12 g, using 6% MeOH in DCM+0.2% NH₄OH as eluent to give acolorless solid (16.86 mg, 83%). ES+APCI MS m/z 561.2 [M+H]⁺.

Example 2081-(4-(2-(3-((3R,4S)-3,4-difluoropyrrolidin-1-yl)propoxy)-7-(3-hydroxynaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Step A: 3-((3R,4S)-3,4-difluoropyrrolidin-1-yl)propan-1-ol

A mixture of (3R,4S)-3,4-difluoropyrrolidine hydrochloride (200 mg, 1.39mmol), 3-bromopropan-1-ol (126 μL, 1.39 mmol, 1.0 eq.), potassiumcarbonate (577 mg, 4.18 mmol, 3 eq.), sodium iodide (209 mg, 1.39 mmol,1 eq.) and acetonitrile (2 mL) in a 7-mL vial was flushed with N₂. Thevial was capped and the reaction mixture was stirred at room temperaturefor 2 days. The mixture was diluted with water (2 mL) and extracted withether (15 mL). The ether solution was washed with brine, dried overNa₂SO₄ and decanted into a pear-shaped flask. Trifluoroacetic acid (107μL, 1 eq) was next added and the mixture was evaporated and dried invacuo. The residue was diluted with water (0.5 mL) and washed with ether(5 mL). To the aqueous layer was added diethyl ether (15 mL) followed by10M NaOH (0.2 mL, 5 mmol) and the mixture was stirred for 1 hour. Theorganic layer was separated and dried over solid KOH, filtered through acotton plug and evaporated under N₂ to give a colorless oil (80 mg, 35%)which was used crude in the next reaction.

Step B: Benzyl4-(2-(3-((3R,4S)-3,4-difluoropyrrolidin-1-yl)propoxy)-7-(3-(methoxymethoxy)naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate

A mixture of benzyl4-(2-chloro-7-(3-(methoxymethoxy)naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(75 mg, 0.13 mmol), crude 2-(4,4-difluoropiperidin-1-yl)ethan-1-ol (65mg, 0.39 mmol), cesium carbonate (213 mg, 0.65 mmol, 5 eq.) and dioxane(0.5 mL) in a 1.7-mL vial was purged with nitrogen. The vial was cappedand stirred at 110° C. over the weekend. The reaction mixture was cooledto room temperature and divided between EtOAc (15 mL) and water (5 mL)and the layers separated. The organic layer was washed with brine, driedover Na₂SO₄ and evaporated in vacuo. The product was purified bychromatography on silica, Redisep 24 g, using 3% MeOH in DCM as eluentto give a colorless solid (46 mg, 50%). ES+APCI MS m/z 703.3 [M+H]⁺.

Step C:1-(4-(2-(3-((3R,4S)-3,4-difluoropyrrolidin-1-yl)propoxy)-7-(3-(methoxymethoxy)naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

A mixture of benzyl4-(2-(3-((3R,4S)-3,4-difluoropyrrolidin-1-yl)propoxy)-7-(3-(methoxymethoxy)naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(46 mg, 0.065 mmol), palladium on carbon (15 mg, Degussa Type, 10 wt %,50% H₂O), EtOH (1 mL) and THF (1 mL) was purged with hydrogen andstirred under H₂ atmosphere (rubber balloon) for 3 hours. The reactionmixture was diluted with EtOH (3 mL), filtered through Celite and thecelite washed with EtOH (2×2 mL). The combined organics were evaporatedin vacuo. The residue was dissolved in DCM (3 mL) and cooled in anice-salt bath with stirring. Triethylamine (0.02 mL) was next addedfollowed by addition of acryloyl chloride (7 μL, 2 eq.). After 1 min at−10° C. the reaction was quenched with NH₄OH (0.03 mL) and evaporated invacuo. The residue was dissolved in DCM (3 mL), filtered and purified bychromatography on silica gel, Redisep 12 g, using 5% MeOH in DCM aseluent to give a colorless solid (29 mg, 71%). ES+APCI MS m/z 623.3[M+H]⁺.

Step D:1-(4-(2-(3-((3R,4S)-3,4-difluoropyrrolidin-1-yl)propoxy)-7-(3-hydroxynaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-ylprop-2-en-1-one

To a stirred solution of1-(4-(2-(3-((3R,4S)-3,4-difluoropyrrolidin-1-yl)propoxy)-7-(3-(methoxymethoxy)naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one(29 mg, 0.047 mmol) in a mixture of MeOH and THE 1:1 (2 mL) was added 6Maqueous HCl (0.2 mL) and the solution was heated with stirring at 50° C.for 1.5 h. The reaction mixture was cooled to room temperature, dividedbetween EtOAc (15 mL) and 0.5M Na₂CO₃ (10 mL) and the layers separated.The organic layer was washed with brine (3 mL), dried over Na₂SO₄ andevaporated in vacuo. The residue was purified by chromatography onsilica, Redisep 12 g, using 5% MeOH in DCM as eluent to give a colorlesssolid (12.87 mg, 48%). ES+APCI MS m/z 579.2 [M+H]⁺.

Example 2091-(4-(7-(5-methyl-1H-indol-4-yl)-2-(3-morpholinopropoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Step A: 4-bromo-5-methyl-1-(triisopropylsilyl)-1H-indole

A solution of 4-bromo-5-methyl-1H-indole (100 mg, 0.476 mmol) in dry THE(2 mL) under nitrogen was cooled with stirring in an ice-salt bath.Sodium hydride (23 mg 60% in oil, 0.57 mg, 1.2 eq.) was added and themixture was stirred for 30 min at −5° C., then 1 h at room temperature(gas evolution ceased). Chlorotriisopropylsilane (0.10 mL, 0.48 mmol, 1eq.) was next added and the reaction mixture was stirred at r.t. for 2hours. The reaction was divided between EtOAc (15 mL) and water (10 mL)and the layers separated. The organic layer was washed with water (5mL), brine (5 mL), dried over Na₂SO₄ and evaporated in vacuo. Theresidue was purified on silica gel using hexanes as eluent to giveproduct. (107 mg, 63%).

Step B: Benzyl4-(7-(5-methyl-1-(triisopropylsilyl)-1H-indol-4-yl)-2-(3-morpholinopropoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate

A stirred mixture of tris(dibenzylideneacetone)dipalladium (0) (17 mg,0.019 mmol) and (+/−)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (24mg, 0.038 mmol) in dry degassed toluene (0.5 mL) under nitrogen washeated to 100° C. for 15 minutes. The mixture was cooled to roomtemperature and solid sodium-t-butoxide (37 mg, 0.38 mmol) addedfollowed by addition of a solution of4-bromo-5-methyl-1-(triisopropylsilyl)-1H-indole (90 mg, 0.25 mmol) andbenzyl4-(2-(3-morpholinopropoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(94 mg, 0.19 mmol) in dry degassed toluene (0.5 mL). The reaction flaskwas closed and heated to 100° C. overnight. The reaction mixture wascooled to room temperature, divided between EtOAc (15 mL) and water (5mL) and the layers separated. The organic layer was washed with brine,dried over Na₂SO₄ and evaporated in vacuo. The product was purified bychromatography on silica gel, Redisep 24 g, using 3 to 5% MeOH indichloromethane as eluent to give a light-yellow solid (28 mg, 19%).ES+APCI MS m/z 782.3 [M]⁺.

Step C:1-(4-(7-(5-methyl-H-indol-4-yl)-2-(3-morpholinopropoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

A mixture of benzyl4-(7-(5-methyl-1-(triisopropylsilyl)-1H-indol-4-yl)-2-(3-morpholinopropoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(46 mg, 0.065 mmol), palladium on carbon (35 mg, Degussa Type, 10 wt %,50% H₂O) in EtOH (1 mL) and THF (1 mL) was purged with hydrogen andstirred under H₂ atmosphere (rubber balloon) overnight. The reactionmixture was diluted with dioxane (3 mL), filtered through celite and thecelite washed with dioxane (2×2 mL). The combined organics wereevaporated in vacuo and dried under high vacuum. The residue wasdissolved in THF (1 mL) under N₂, then 1M tetra-n-butylammonium fluoridein THF (0.07 mL, 2 eq.) was added with stirring and the solution stirredat 0° C. for 15 minutes. The reaction mixture was divided between ether(15 mL) and water (5 mL) and the layers separated. The organic layer waswashed with water (3 mL), brine (3 mL), dried over Na₂SO₄ and evaporatedunder nitrogen. The crude product was dissolved in DCM (3 mL) and cooledin an ice-salt-dry ice bath (−20° C.) with stirring. Triethylamine (10μL, 2 eq.) was next added followed by acryloyl chloride (2 μL, 0.75eq.). After 10 min at −20° C. the reaction was quenched with NH₄OH (0.03mL). and evaporated in vacuo. The product was purified by chromatographyon silica gel column using 5% MeOH/DCM+0.1% NH₄OH as eluent to give acolorless solid (3.69 mg, 19%). ES+APCI MS m/z 546.3 [M+H]⁺.

Example 2102-(1-acryloyl-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(2-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

Step A: Tert-butyl2-chloro-4-(3-(cyanomethyl)piperazin-1-yl)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate

tert-butyl2,4-dichloro-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate (8.00g, 26.3 mmol), Hunig's base (22.9 ml, 132 mmol) and2-(piperazin-2-yl)acetonitrile dihydrochloride (5.21 g, 26.3 mmol) wereplaced in DMA (75 mL) and stirred at room temperature for 20 minutes.Water was added to the reaction and the mixture was extracted with EtOAc(3×100 mL). The extracts were combined and washed with water (3×50 mL),dried with sodium sulfate, filtered and concentrated to provide crudematerial that was used as is. ES+APCI MS m/z 393.3 [M+H]⁺.

Step B: tert-butyl4-(4-((benzyloxy)carbonyl)-3-(cyanomethyl)piperazin-1-yl)-2-chloro-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate

tert-butyl2-chloro-4-(3-(cyanomethyl)piperazin-1-yl)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate(10.5 g, 26.7 mmol) and TEA (5.6 ml, 40.1 mmol) were placed in THE (100mL) and cooled to 0° C. Benzyl carbonochloridate (5.7 ml, 40.1 mmol) wasadded and the reaction was stirred at 0° C. for 30 minutes. Water wasadded to the reaction and the mixture was extracted with DCM (3×50 mL)and the extracts were combined and concentrated. The residue waspurified by silica gel (0-60% EtOAc in hexane as eluent) to providetert-butyl4-(4-((benzyloxy)carbonyl)-3-(cyanomethyl)piperazin-1-yl)-2-chloro-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate(12.9 g, 24.5 mmol, 92% yield). ES+APCI MS m/z 527.1 [M+H]⁺.

Step C: Tert-butyl4-(4-((benzyloxy)carbonyl)-3-(cyanomethyl)piperazin-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate

In a sealed tubetert-butyl4-(4-((benzyloxy)carbonyl)-3-(cyanomethyl)piperazin-1-yl)-2-chloro-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate(1.50 g, 2.85 mmol) was dissolved in dioxane (1.42 ml, 2.85 mmol) andtreated with milled cesium carbonate (1.85 g, 5.69 mmol) and(2S)-1-Ethyl-2-pyrrolidinyl]methanol (1.64 g, 14.2 mmol). The tube wasthen capped and heated to 90° C. for 24 hr. The reaction was cooled toroom temperature and water was added. The mixture was extracted with DCM(3×25 mL), and the combined organics concentrated in vacuo. The residuewas purified by silica gel (0-12% MeOH in DCM w/0.2% NH₄OH as eluent) togive tert-butyl4-(4-((benzyloxy)carbonyl)-3-(cyanomethyl)piperazin-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate(831 mg, 1.37 mmol, 48% yield). ES+APCI MS m/z 606.2 [M+H]⁺.

Step D: benzyl2-(cyanomethyl)-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate

tert-butyl4-(4-((benzyloxy)carbonyl)-3-(cyanomethyl)piperazin-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate(831 mg, 1.37 mmol) was placed in DCM (15 mL) and TFA (2114 μL, 27.4mmol) was added and the reaction was stirred at rt for hr. The reactionwas concentrated. Saturated bicarbonate was added and the mixture wasextracted with DCM (3×25 mL). The extracts were combined, dried withsodium sulfate, filtered and concentrated to give benzyl2-(cyanomethyl)-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(665 mg, 1.32 mmol, 96% yield) which was used as is. ES+APCI MS m/z506.2 [M+H]⁺.

Step E: Benzyl2-(cyanomethyl)-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(2-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate

To a vial was added cesium carbonate (103 mg, 0.316 mmol), benzyl2-(cyanomethyl)-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(80 mg, 0.158 mmol), Rhuphos Pd G3 (13.2 mg, 0.016 mmol),1-bromo-2-(trifluoromethyl)benzene (53.4 mg, 0.237 mmol) and 1,4-dioxane(1582 μL, 0.158 mmol) and the vial was degassed with Ar, sealed thenheated to 70° C. for 24 hours. Water and saturated NH₄Cl were added tothe reaction and the mixture was extracted with DCM. The organic layerconcentrated in vacuo. The resulting residue was purified by silica gel(0-12% MeOH in DCM w/0.2% NH₄OH as eluent) to provide benzyl2-(cyanomethyl)-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(2-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(20.5 mg, 0.032 mmol, 20% yield). ES+APCI MS m/z 650.3 [M+H]⁺.

Step F:2-(4-(2-(((S)-1-methylpyrrolidin-2-ylmethoxy)-7-(2-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

To a solution of benzyl2-(cyanomethyl)-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(2-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(20.5 mg, 0.032 mmol) in EtOH (316 μL, 0.0316 mmol) and THE (316 μL,0.032 mmol) was added palladium (16.8 mg, 0.008 mmol) (Degussa Type, 10wt %, 50% H₂O) and then an atmosphere of H₂ was introduced via vacuumfollowed by balloon pressure and was stirred for 2 hours. The mixturewas then diluted with MeOH and filtered through GF/F paper. The filtratewas then concentrated to provide desired product which was used as is.ES+APCI MS m/z 516.2 [M+H]⁺.

Step G:2-(1-acryloyl-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(2-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

2-(4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(2-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile(16.3 mg, 0.032 mmol) and triethylamine (13.2 μL, 0.095 mmol) wereplaced in CH2Cl2 (316 μL, 0.032 mmol) and cooled to 0° C. Acryloylchloride (632 μL, 0.063 mmol) was added (freshly prepared 0.1M solutionin DCM) and the reaction was stirred for 1 hour at 0° C. The mixture wasconcentrated and the resulting residue was purified by reverse phasechromatography (0-50% ACN:water w/0.1% TFA) to provide desired product(18.9 mg, 0.027 mmol, 87% yield). ES+APCI MS m/z 570.3 [M+H]⁺.

Example 2112-(1-acryloyl-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(2-(trifluoromethoxy)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

Synthesized according to Example 210, Steps E-G using1-bromo-2-(trifluoromethoxy)benzene in place of1-bromo-2-(trifluoromethyl)benzene in Step E. ES+APCI MS m/z 586.3[M+H]⁺.

Example 2122-(1-acryloyl-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(4-(trifluoromethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

Synthesized according Example 210, Steps E-G using3-bromo-4-(trifluoromethyl)pyridine in place of1-bromo-2-(trifluoromethyl)benzene in Step E. ES+APCI MS m/z 571.3[M+H]⁺.

Example 2131-(4-(7-(5-hydroxy-2,3-dimethylphenyl)-2-(3-morpholinopropoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Step A: 3-bromo-4,5-dimethylphenol

In a sealed tube DPPE (0.431 g, 1.08 mmol),4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.73 g, 13.5 mmol),(1,5-Cyclooctadiene)-eta5-indenyl)iridium(I) (0.449 g, 1.08 mmol) and1-bromo-2,3-dimethylbenzene (1.00 g, 5.40 mmol) were placed incyclohexane (6 mL) and was heated to 100° C. for 50 hr. The reaction wasconcentrated down and brought up in acetone (5 mL) and oxzone (3.32 g,5.40 mmol) was added and stirred for 10 min. The reaction was quenchedwith saturated NaHSO3 and was extracted with DCM (3×20 ml). The extractswere washed with brine, water and concentrated. The residue was passedthrough a plug of silica eluting with DCM to provide3-bromo-4,5-dimethylphenol (238 mg, 1.18 mmol, 22% yield).

Step B: 1-bromo-5-(methoxymethoxy)-2,3-dimethylbenzene

Was prepared according to the preparation for Intermediate 3substituting the 3-bromo-4,5-dimethylphenol for 2-bromo-3-fluorophenol.

Step C

1-(4-(7-(5-hydroxy-2,3-dimethylphenyl)-2-(3-morpholinopropoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one2,2,2-trifluoroacetate: was prepared according to Example 1 Steps C-Fsubstituting Intermediate 25 for benzyl4-(5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylateand 1-bromo-5-(methoxymethoxy)-2,3-dimethylbenzene for1-bromo-3-(methoxymethoxy)naphthalene in Step C. ES+APCI MS m/z 537.3[M+H]⁺.

Example 2141-(4-(7-(5-hydroxy-2-((trifluoromethyl)thio)phenyl)-2-(3-morpholinopropoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Step A: 3-bromo-4-((trifluoromethyl)thio)phenol

In a sealed tube 3-bromophenol (575 mg, 3.32 mmol) andN,4-dimethyl-N-(trifluoromethyl)benzenesulfonamide (1010 mg, 3.99 mmol)were placed in dry DCE (6 mL). Triflic acid (295 μL, 3.32 mmol) wasadded slowly and the reaction was then heated to 80° C. for 18 hours.The reaction was cooled and the solvent was removed under vacuum and theresulting residue was purified by silica gel (0-20% EtOAc in hexanes) toprovide 3-bromo-4-((trifluoromethyl)thio)phenol (650 mg, 2.38 mmol, 72%yield)

Step B: (2-bromo-4-(methoxymethoxy)phenyl)(trifluoromethyl)sulfane

Was prepared according to the preparation for Intermediate 3substituting the 3-bromo-4-((trifluoromethyl)thio)phenol for2-bromo-3-fluorophenol.

Step C:1-(4-(7-(5-hydroxy-2-((trifluoromethylthio)phenyl)-2-(3-morpholinopropoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Synthesized according to Example 1 Step C-F substituting Intermediate 25for benzyl4-(5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylateand (2-bromo-4-(methoxymethoxy)phenyl)(trifluoromethyl)sulfane for1-bromo-3-(methoxymethoxy)naphthalene in Step C. ES+APCI MS m/z 609.2[M+H]⁺.

Example 215(R)-1-(4-(2-(2-hydroxy-3-morpholinopropoxy)-7-(3-hydroxynaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Title compound was obtained by SFC chiral resolution of Example 123using a Phenomenex OZ-H column (4.6 mm×250 mm, 5u) and eluting with40-60% MeOH:IPA:DEA (80:20:1) at 4 mL/min. Collecting the first elutingpeak provided the desired compound where the stereochemistry wasarbitrarily assigned. ES+APCI MS m/z 575.2 [M+H]⁺.

Example 216(S)-1-(4-(2-(2-hydroxy-3-morpholinopropoxy)-7-(3-hydroxynaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Title compound was obtained by SFC chiral resolution of Example 123using a Phenomenex OZ-H column (4.6 mm×250 mm, 5u) and eluting with40-60% MeOH:IPA:DEA (80:20:1) at 4 mL/min. Collecting the second elutingpeak provided the desired compound where the stereochemistry wasarbitrarily assigned. ES+APCI MS m/z 575.2 [M+H]⁺.

Example 2171-(4-(2-((1-hydroxy-3-morpholinopropan-2-yl)oxy)-7-(3-hydroxynaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Synthesized according to the method of Example 8, using3-morpholinopropane-1,2-diol in place of(S)-1-(dimethylamino)propan-2-ol in Step B. ES+APCI MS m/z 575.2 [M+H]⁺.

Example 218

2-(1-acryloyl-4-(2-(((2S,4R)-4-hydroxy-1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

Step A: benzyl4-(2-(((2S,4R)-1-(tert-butoxycarbonyl)-4-((tert-butyldimethylsilyl)oxy)pyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate

In a sealed vial, a solution of benzyl4-(2-chloro-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate(150 mg, 0.27 mmol) in dioxane (2712 μL, 0.27 mmol) was sparged withargon and(2S,4R)-4-{[tert-Butyl(dimethyl)silyl]oxy}-2-(hydroxymethyl)pyrrolidine-1-carboxylate(270 mg, 0.81 mmol), Cs₂CO₃ (265 mg, 0.81 mmol), Rhuphos Pd G3 (22.7 mg,0.027 mmol) were sequentially added under argon and sparged for anadditional 5 min. The reaction mixture was capped and heated at 100° C.for 2 hr. Water was added and the mixture was extracted with DCM (3×15mL). The extracts were combined and concentrated and the resultingresidue was purified by silica gel (0-40% EtOAc in hexanes) to providebenzyl4-(2-(((2S,4R)-1-(tert-butoxycarbonyl)-4-((tert-butyldimethylsilyl)oxy)pyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate(113 mg, 0.13 mmol, 49% yield).

Step B: tert-butyl(2S,4R)-4-((tert-butyldimethylsilyl)oxy)-2-(((4-(3-(cyanomethyl)piperazin-1-yl)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)oxy)methyl)pyrrolidine-1-carboxylate

To a solution of benzyl4-(2-(((2S,4R)-1-(tert-butoxycarbonyl)-4-((tert-butyldimethylsilyl)oxy)pyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate(113 mg, 0.133 mmol) in EtOH (1.3 mL, 0.133 mmol) and THF (1.3 mL, 0.133mmol) was added palladium (70.9 mg, 0.033 mmol) (Degussa Type, 10 wt %,50% H₂O) and then an atmosphere of H₂ was introduced via vacuum followedby balloon pressure. The mixture was then stirred at ambient temperaturefor 2 hours. The mixture was then diluted with 1:1 MeOH and THE andfiltered through GF/F paper. The filtrate was then concentrated toprovide crude product which was used as is.

Step C: tert-butyl(2S,4R)-2-(((4-(4-acryloyl-3-(cyanomethyl)piperazin-1-yl)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)oxy)methyl)-4-((tert-butyldimethylsilyl)oxy)pyrrolidine-1-carboxylate

tert-butyl(2S,4R)-4-((tert-butyldimethylsilyl)oxy)-2-(((4-(3-(cyanomethyl)piperazin-1-yl)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)oxy)methyl)pyrrolidine-1-carboxylate(95 mg, 0.13 mmol) and triethylamine (56 μL, 0.40 mmol) were placed inCH2Cl2 (1331 μL, 0.13 mmol) and cooled to 0° C. Acryloyl chloride (2661μL, 0.27 mmol) (freshly prepared 0.1M solution in DCM) was added and thereaction was stirred for 30 min at 0° C. Water was added to the reactionand the mixture was extracted with DCM (3×15 mL). The extracts werecombined and concentrated to provide crude material which was used asis.

Step D:2-(1-acrylol-4-(2-(((2S,4R)-4-((tert-butyldimethylsilyl)oxy)pyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

tert-butyl(2S,4R)-2-(((4-(4-acryloyl-3-(cyanomethyl)piperazin-1-yl)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)oxy)methyl)-4-((tert-butyldimethylsilyl)oxy)pyrrolidine-1-carboxylate(92 mg, 0.12 mmol) was placed in DCM (3 mL) and TFA (92 μL, 1.2 mmol)was added and the reaction was stirred at room temperature for 2 hours.Saturated bicarbonate was added to the reaction and the mixture wasextracted with DCM (3×15 mL). The extracts were combined, dried withsodium sulfate, filtered and concentrated to give crude material thatwas used as is.

Step E:2-(1-acrylol-4-(2-(((2S,4R)-4-((tert-butyldimethylsilyl)oxy)-1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-ylacetonitrile

2-(1-acryloyl-4-(2-(((2S,4R)-4-((tert-butyldimethylsilyl)oxy)pyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile(80 mg, 0.12 mmol), formaldehyde (45.0 μL, 0.60 mmol) and Na(OAc)₃BH(50.8 mg, 0.24 mmol) were placed in THE (2 mL) and stirred for 2 hrs.Saturated bicarbonate was added and the mixture was extracted with 10%MeOH in DCM (3×15 mL). The extracts were combined, dried with sodiumsulfate, and concentrated to provide crude material which was used asis.

Step F:2-(1-acrylol-4-(2-(((2S,4R)-4-hydroxy-1-methylpyrrolidin-2-ylmethoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile2,2,2-trifluoroacetate

2-(1-acryloyl-4-(2-(((2S,4R)-4-((tert-butyldimethylsilyl)oxy)-1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile(81 mg, 0.119 mmol) was placed in DCM (5 mL) and HCl (594 μL, 2.38 mmol)was added and the reaction was stirred for hr. The reaction wasconcentrated and the material was purified by reverse phasechromatography (0-50% ACN:water with 0.1% TFA) to provide2-(1-acryloyl-4-(2-(((2S,4R)-4-hydroxy-1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile(38.9 mg, 0.057 mmol, 48% yield). ES+APCI MS m/z 568.3 [M+H]⁺.

Example 2191-(4-(2-((1,4-dimethylpiperazin-2-yl)methoxy)-7-(3-hydroxynaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Title compound was prepared the same as Example 127, substituting(1,4-Dimethyl-2-piperazinyl)methanol in place of N-Methyl-L-prolinol inStep D. ES+APCI MS m/z 558.3 [M+H]⁺.

Example 2202-(1-acryloyl-4-(2-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

Step A: benzyl4-(2-chloro-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate

To a solution of tert-butyl4-(4-((benzyloxy)carbonyl)-3-(cyanomethyl)piperazin-1-yl)-2-chloro-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate(4.00 g, 7.59 mmol) in DCM (25.3 ml, 7.59 mmol) was addedtrifluoroacetic acid (17.4 ml, 227.7 mmol) and the reaction was stirredat room temperature for 3 hours. The reaction was concentrated to athick oil. Saturated bicarbonate was added slowly and the mixture wasextracted with 10% MeOH in DCM (3×50 mL). The extracts were combined,dried with sodium sulfate and concentrated to provide the desiredproduct (3.24 g, 7.6 mmol, 100% yield) which was used as is. ES+APCI MSm/z 506.2 [M]⁺.

Step B: Benzyl4-(2-chloro-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate

To around bottomed flask was added cesium carbonate (8.01 g, 24.6 mmol),benzyl4-(2-chloro-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate(3.5 g, 8.2 mmol), 1-bromonaphthalene (4.6 ml, 32.8 mmol) and RuPhos PdG3 (1.0 g, 1.23 mmol). After evacuating the flask, 1,4-dioxane (82.0 ml,8.20 mmol) was added through a septum under argon flow. Argon wasbubbled through the mixture for 5 minutes and then the mixture washeated to 70° C. overnight. The reaction was cooled and water was addedand extracted with ethyl acetate and the organics concentrated in vacuo.The yellow solids were dissolved in minimal DCM and purified by silicachromatography (25-60% EtOAc in hexanes) to provide benzyl4-(2-chloro-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate(2.0 g, 3.6 mmol, 44.1% yield). ES+APCI MS m/z 553.2 [M]⁺.

Step C: benzyl4-(2-(((2S,4R)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate

In a vial benzyl4-(2-chloro-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate(120 mg, 0.22 mmol) was dissolved in dioxane (108 μL, 0.217 mmol) andtreated with cesium carbonate (141 mg, 0.434 mmol), and(2S,4R)-1-(tert-Butoxycarbonyl)-4-fluoro-2-hydroxymethylpyrrolidine(47.6 mg, 0.217 mmol). The tube was then capped and heated to 90° C. for12 hours. The reaction was filtered through GF/F paper and concentrated.The residue was purified by silica chromatography (0-6% MeOH in DCM).ES+APCI MS m/z 736.3 [M+H]⁺.

Step D: benzyl2-(cyanomethyl)-4-(2-(((2S,4R)-4-fluoropyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate

To a solution of benzyl4-(2-(((2S,4R)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate(125 mg, 0.170 mmol) in DCM (170 μL, 0.170 mmol) was addedtrifluoroacetic acid (195 μL, 2.55 mmol) and the reaction stirred at RTfor 2 hr. The organics were washed with sodium bicarbonate and theaqueous layer was back extracted with DCM. The combined organic layerswere concentrated and used without further purification. ES+APCI MS m/z636.3 [M+H]⁺.

Step E: benzyl2-(cyanomethyl)-4-(2-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate

To a solution of benzyl2-(cyanomethyl)-4-(2-(((2S,4R)-4-fluoropyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(105 mg, 0.1652 mmol) in DCE (3303 μL, 0.1652 mmol) was addedformaldehyde (124.1 μL, 1.652 mmol) (37% in water) followed by sodiumtriacetoxyborohydride (175.0 mg, 0.8258 mmol). The mixture was stirredvigorously at RT for 2.5 h. The mixture was treated with saturatedsodium bicarbonate (30 mL), stirred for 10 min then extracted with DCM(3×10 mL). The combined organic phases were dried over sodium sulfate,filtered and concentrated and used as is in the next reaction. ES+APCIMS m/z 650.3 [M+H]⁺.

Step F:2-(4-(2-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-ylmethoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

To a solution of benzyl2-(cyanomethyl)-4-(2-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(85 mg, 0.13 mmol) in EtOH (1308 μL, 0.13 mmol) and THF (1308 μL, 0.13mmol) was added palladium (70 mg, 0.033 mmol) (Degussa Type, 10 wt %,50% H₂O) and then an atmosphere of H₂ was introduced via vacuum followedby balloon pressure. The mixture was then stirred at ambient temperatureovernight. The mixture was then diluted with MeOH and filtered throughGF/F paper. The filtrate was then concentrated to provide2-(4-(2-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile.ES+APCI MS m/z 516.3 [M+H]⁺.

Step G:2-(1-acrylol-4-(2-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-ylmethoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

To a suspension of2-(4-(2-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile(65 mg, 0.126 mmol) in DCM (1261 μL, 0.126 mmol) at 0° C. was addedacryloyl chloride (2521 μL, 0.252 mmol) (freshly prepared 0.1M solutionin DCM) followed by triethylamine (35.1 μL, 0.252 mmol). The reactionwas then stirred at 0° C. for 45 minutes. The reaction was concentratedand purified by reverse phase chromatography (0-50% CAN:water with 0.1%TFA) to provide the title compound. ES+APCI MS m/z 570.3 [M+H]⁺.

Example 2212-(1-acryloyl-4-(2-(((2S,4S)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

Synthesized according to the method of Example 220, Step C-G, usingtert-butyl (2S,4S)-4-fluoro-2-(hydroxymethyl)pyrrolidine-1-carboxylatein place of tert-butyl(2S,4R)-4-fluoro-2-(hydroxymethyl)pyrrolidine-1-carboxylate in Step C.ES+APCI MS m/z 570.3 [M+H]⁺.

Example 2222-(1-acryloyl-4-(2-(((2S,4S)-4-methoxy-1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

Title compound was prepared following Example 220 (Steps C-G),substituting tert-butyl(2S,4S)-2-(hydroxymethyl)-4-methoxypyrrolidine-1-carboxylate for(2S,4R)-1-(tert-Butoxycarbonyl)-4-fluoro-2-hydroxymethylpyrrolidine inStep C. ES+APCI MS m/z 582.3 [M+H]⁺.

Example 2232-(1-acryloyl-4-(2-(((S)-4-methylpiperazin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

Steps A-F:2-(1-acrylol-4-(2-(((S)-4-methylpiperazin-2-ylmethoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

Title compound was prepared following Example 220 (Steps C-G),substituting tert-butyl(S)-2-(hydroxymethyl)-4-methylpiperazine-1-carboxylate for(2S,4R)-1-(tert-Butoxycarbonyl)-4-fluoro-2-hydroxymethylpyrrolidine inStep C. ES+APCI MS m/z 567.3 [M+H]⁺.

Example 2242-(1-acryloyl-4-(2-(((R)-4-methylpiperazin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

Title compound was prepared following Example 220 (Steps C-G),substituting tert-butyl(R)-2-(hydroxymethyl)-4-methylpiperazine-1-carboxylate for tert-butyl(S)-2-(hydroxymethyl)-4-methylpiperazine-1-carboxylate in Step C.ES+APCI MS m/z 567.3 [M+H]⁺.

Example 2252-(1-acryloyl-4-(7-(5-fluoro-2-(trifluoromethoxy)phenyl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

Title compound was prepared as in Example 210 Steps E-G, substituting2-bromo-4-fluoro-1-(trifluoromethoxy)benzene for1-bromo-2-(trifluoromethyl)benzene in step E. ES+APCI MS m/z 604.3[M+H]⁺.

Example 2262-(1-acryloyl-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(2-(trifluoromethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

Title compound was prepared as in Example 210 Steps E-G, substituting3-bromo-2-(trifluoromethyl)pyridine for1-bromo-2-(trifluoromethyl)benzene in Step E. ES+APCI MS m/z 571.3[M+H]⁺.

Example 2272-(1-acryloyl-4-(7-(2-fluorophenyl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

Title compound was prepared as in Example 210 Steps E-G, substituting1-bromo-2-fluorobenzene for 1-bromo-2-(trifluoromethyl)benzene in stepE. ES+APCI MS m/z 520.3 [M+H]⁺.

Example 2282-(1-acryloyl-4-(7-(2,3-dimethylphenyl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

Title compound was prepared as in Example 210 Steps E-G, substituting1-bromo-2,3-dimethylbenzene for 1-bromo-2-(trifluoromethyl)benzene inStep E. ES+APCI MS m/z 530.3 [M+H]⁺.

Example 2292-(1-acryloyl-4-(7-(2-chlorophenyl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

Title compound was prepared as in Example 210 Steps E-G, substituting1-bromo-2-chlorobenzene for 1-bromo-2-(trifluoromethyl)benzene in stepE. ES+APCI MS m/z 536.2 [M]⁺.

Example 2302-(1-acryloyl-4-(7-(3-fluoro-2-(trifluoromethyl)phenyl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

Title compound was prepared as in Example 210 Steps E-G, substituting1-bromo-3-fluoro-2-(trifluoromethyl)benzene for1-bromo-2-(trifluoromethyl)benzene in Step E. ES+APCI MS m/z 588.3[M+H]⁺.

Example 2312-(1-acryloyl-4-(2-(3-hydroxypropoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

Step A: benzyl2-(cyanomethyl)-4-(2-(3-hydroxypropoxy)-7-(naphthalen-1-yl)-5,6,7,8tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate

Title compound was prepared as in Example 220 Step C, substitutingpropane-1,3-diol for(2S,4R)-1-(tert-Butoxycarbonyl)-4-fluoro-2-hydroxymethylpyrrolidine.ES+APCI MS m/z 593.3 [M+H]⁺.

Step B: benzyl4-(2-(3-((tert-butyldimethylsilyl)oxy)propoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate

To a vial was added benzyl2-(cyanomethyl)-4-(2-(3-hydroxypropoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(77.6 mg, 0.131 mmol), which was dissolved in DCM (655 μL, 0.131 mmol).The mixture was cooled to 0° C. and then triethylamine (36.5 μL, 0.262mmol) was added followed by 4-(dimethylamino)-pyridine (4.80 mg, 0.04mmol). Then tert-butyldimethylsilyl chloride (29.6 mg, 0.196 mmol) wasadded and the mixture was stirred overnight while warming to roomtemperature. The reaction mixture was poured onto a saturated brinesolution (5 ml) and the mixture extracted twice with EtOAc (10 mL). Theorganic phases were dried over sodium sulfate, filtered andconcentrated. The crude reaction product was used as is. ES+APCI MS m/z707.4 [M+H]+.

Step C:2-(4-(2-(3-((tert-butyldimethylsilyloxy)propoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

To a solution of benzyl4-(2-(3-((tert-butyldimethylsilyl)oxy)propoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate(106 mg, 0.150 mmol) in EtOH (1499 μL, 0.150 mmol) and THE (1499 μL,0.150 mmol) was added palladium (79.8 mg, 0.0375 mmol) (Degussa Type, 10wt %, 50% H₂O) and then an atmosphere of H₂ was introduced via vacuumfollowed by balloon pressure. The mixture was then stirred at ambienttemperature overnight. The mixture was then diluted with MeOH andfiltered through GF/F paper. The filtrate was then concentrated to acolorless solid that was used without further purification. ES+APCI MSm/z 573.3 [M+H]+.

Step D:2-(1-acrylol-4-(2-(3-((tert-butyldimethylsilylox)propoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

To a suspension of2-(4-(2-(3-((tert-butyldimethylsilyl)oxy)propoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile(75 mg, 0.131 mmol) in DCM (1309 μL, 0.131 mmol) at −78° C. was addedacryloyl chloride (2619 μL, 0.262 mmol) (freshly prepared 0.1M solutionin DCM) followed by triethylamine (36.5 μL, 0.262 mmol). The reactionwas then stirred at 0° C. for 30 minutes. The reaction was concentratedand used crude in the next reaction. ES+APCI MS m/z 627.4 [M+H]+.

Step E:2-(1-acrylol-4-(2-(3-hydroxypropoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

To a solution of2-(1-acryloyl-4-(2-(3-((tert-butyldimethylsilyl)oxy)propoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile(90 mg, 0.14 mmol) in DCM (1436 μL, 0.14 mmol) was added hydrochloricacid (4.0 M in 1,4-dioxane) (359 μL, 1.4 mmol) at 0° C. The reaction wasstirred for 30 min at which point it was quenched with saturated sodiumbicarbonate and extracted into 10% IPA in CHCl₃ (3×15 ml). The combinedorganic layers were concentrated and the residue was purified by reversephase chromatography (0-95% ACN:H₂O with 0.1TFA). ES+APCI MS m/z 513.2[M+H]+.

Example 2321-(4-(7-(3-chloro-2-fluoro-5-hydroxyphenyl)-2-(3-morpholinopropoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

The title compound was prepared according to Example 1 Step C-Fsubstituting Intermediate 25 for benzyl4-(5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylateand 1-bromo-3-chloro-2-fluoro-5-(methoxymethoxy)benzene for1-bromo-3-(methoxymethoxy)naphthalene in Step C. ES+APCI MS m/z 561.2[M]+.

Example 2332-(1-acryloyl-4-(2-(((S)-1-ethylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

2-(1-acryloyl-4-(2-(((S)-1-ethylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-ylacetonitrile

This compound was prepared following Example 147 substituting(S)-(1-ethylpyrrolidin-2-yl)methanol for N-Methyl-L-prolinol for[(2S)-1-methylpyrrolidin-2-yl]methanol in Step F. ES+APCI MS m/z 566.3[M+H]⁺.

Example 2342-((S)-1-acryloyl-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

Step A: 1-Benzyl 4-(tert-butyl)(R)-2-(hydroxymethyl)piperazine-1,4-dicarboxylate

To a stirred biphasic solution of (R)-1-Boc-3-hydroxymethylpiperazine(5.00 g, 23.1 mmol) and NaHCO₃ (5.83 g, 69.4 mmol) in ethyl acetate(46.2 ml) and water (46.2 ml) at 0° C. was added benzyl chloroformate(4.95 ml, 34.7 mmol) dropwise. The reaction mixture was stirred atambient temperature overnight. The reaction mixture was diluted withEtOAc (50.0 ml) and the organic layer was separated, dried (Na₂SO₄) andconcentrated. The crude product was purified by flash chromatographyeluting with 10-50% EtOAc/hexanes gradient to afford the title compound(7.62 g, 21.7 mmol, 94.1%). ESI MS m/z 251.1 [M-Boc+H]+.

Step B. 1-Benzyl 4-(tert-butyl)(R)-2-(((methylsulfonyl)oxy)methyl)piperazine-1,4-dicarboxylate

To a solution of 1-benzyl 4-(tert-butyl)(R)-2-(hydroxymethyl)piperazine-1,4-dicarboxylate (1.69 g, 4.83 mmol)and triethylamine (1.01 ml, 7.25 mmol) in CH2C2 (32.2 ml) at 0° C. wasadded dropwise MsCl (0.561 ml, 7.25 mmol) neat and the resulting mixturewas stirred at RT for 10 min. The reaction mixture was poured into aseparatory funnel, diluted with ethyl acetate, then washed sequentiallywith 1N HCl, water, NaHCO₃ (sat.), and brine to afford the titlecompound (1.9 g, ˜100%, used as crude material in next step). ESI MS m/z329.1 [M-Boc+H]+.

Step C. 1-Benzyl 4-(tert-butyl)(S)-2-(cyanomethyl)piperazine-1,4-dicarboxylate

A solution of 1-benzyl 4-(tert-butyl)(R)-2-(((methylsulfonyl)oxy)methyl)piperazine-1,4-dicarboxylate (2.10 g,4.90 mmol), sodium cyanide (0.480 g, 9.80 mmol) in DMA (49.0 ml) washeated at 55° C. for 1 day. The reaction was followed by HPLC (15 minmethod). The mixture was partitioned between EtOAc/brine, and theorganic layer was washed with brine (3×), dried over MgSO4 andconcentrated. The residue was purified by flash chromatography elutingwith 0-100% EtOAc/hexanes gradient to afford the title compound (1.40 g,3.90 mmol, 79.5%). Aqueous layers were basified and disposed of incyanide waste stream. ESI MS m/z 260.1 [M-Boc+H]+.

Step D. Benzyl (S)-2-(cyanomethyl)piperazine-1-carboxylate hydrochloride

1-Benzyl 4-(tert-butyl) (S)-2-(cyanomethyl)piperazine-1,4-dicarboxylate(5.32 g, 14.8 mmol) was placed in CH2C2 (25 mL) and HCl (4.0 N indioxane, 18.5 ml, 74.0 mmol) was added and the reaction was stirred atambient temperature for I d. The reaction mixture was concentrated toafford the title compound (4.3 g, 99%). ESI MS m/z 260.1 [M+H]⁺.

Step E. Tert-Butyl(S)-4-(4-((benzyloxy)carbonyl)-3-(cyanomethyl)piperazin-1-yl)-2-chloro-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate

A solution of benzyl (S)-2-(cyanomethyl)piperazine-1-carboxylate (1.01g, 3.89 mmol), tert-butyl2,4-dichloro-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate (1.18g, 3.89 mmol) and DIEA (1.36 ml, 7.79 mmol) in DMSO (19.5 ml) was heatedat 50° C. for 1 day. The reaction mixture was partitioned between ethylacetate and brine and the organics separated. The organic phase waswashed with brine (3×), dried over MgSO4 and concentrated to afford thetitle compound (1.63 g, 3.09 mmol, 79.4%). ESI MS m/z 527.2 [M+H]+.

Step F. tert-butyl4-((S)-4-((benzyloxy)carbonyl)-3-(cyanomethyl)piperazin-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate

In 250 mL heavy-wall round bottom flask with a PTFE screw cap was addeda solution of tert-butyl(S)-4-(4-((benzyloxy)carbonyl)-3-(cyanomethyl)piperazin-1-yl)-2-chloro-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate(1.64 g, 3.11 mmol) in dioxane (31.1 ml) and the mixture was spargedwith argon. To the mixture was added sequentially(S)-(1-methylpyrrolidin-2-yl)methanol (1.08 g, 9.34 mmol), Cs₂CO₃ (3.04g, 9.34 mmol) and Ruphos-Pd Gen3 catalyst (0.260 g, 0.311 mmol) underargon and sparged for an additional 5 min. The reaction mixture wascapped and heated at 100° C. for 1 day. The reaction mixture was dilutedwith ethyl acetate and the organics washed with brine (2×). The organiclayer was dried over MgSO4 and concentrated to give a residue that waspurified by flash chromatography eluting with 0-20% (MeOH+2% NH₄OH) inDCM to afford the title compound (1.42 g, 2.34 mmol, 75.3%). ESI MS m/z606.3 [M+H]⁺.

Step G. Benzyl(S)-2-(cyanomethyl)-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylatebis-trifluoroacetate Salt

A solution of tert-butyl4-((S)-4-((benzyloxy)carbonyl)-3-(cyanomethyl)piperazin-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate(38 mg, 0.063 mmol) in CH2Cl2 (627 μl) and TFA (242 μl, 3.1 mmol) wasstirred at room temperature for 1 day. The reaction mixture wasconcentrated and used as bis-TFA salt in the next reaction (46 mg, 0.063mmol, 100%). ESI MS m/z 506.3 [M+H]⁺.

Step H. Benzyl(S)-2-(cyanomethyl)-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate

A suspension of benzyl(S)-2-(cyanomethyl)-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylatebistrifluoroacetate salt (46 mg, 0.063 mmol), 1-bromonaphthalene (39.3mg, 0.190 mmol) and Cs₂CO₃ (61.9 mg, 0.190 mmol) in dioxane (633 μl) wassparged with argon for 5 min. To this mixture was added Ruphos Pd Gen 3(5.29 mg, 0.006 mmol) and the resulting suspension was sparged for anadditional 1 minute with argon. The vial was capped and heated at 100°C. for 2 h. The reaction mixture was partitioned between EtOAc and waterand the aqueous layer was extracted with EtOAc (3×). The combinedorganic layers were dried over MgSO4 and concentrated. The residue waspurified by flash chromatography eluting with 5% MeOH/1% NH₄OH/CH₂Cl₂isocratic to afford the title compound (31.9 mg, 0.050 mmol, 79.8%). ESIMS m/z 632.3 [M+H]+.

Step I.2-((S)-4-(2-(((S)-1-Methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

To a solution of benzyl(S)-2-(cyanomethyl)-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(31 mg, 0.049 mmol) in methanol (981 μl) and THE (981 μl) sparged withnitrogen was added Pd/C (10.4 mg, 0.00491 mmol) and the mixture wasstirred under balloon pressure atmosphere of H₂ for 1 day. The reactionmixture was filtered through a PTFE syringe filter (25 mm) and thefiltrate was concentrated to afford the title compound (23.4 mg, 0.047mmol, 95.8%). ESI MS m/z 498.3 [M+H]+.

Step J.2-((S)-1-Acrylol-4-(2-(((S)-1-methylpyrrolidin-2-ylmethoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

To a solution of2-((S)-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile(23.4 mg, 0.047 mmol) in CH2C2 (470 μl) was added DIEA (41.1 μl, 0.235mmol) then acryloyl chloride (12 μl, 0.141 mmol). The resulting mixturewas stirred at ambient temperature for 15 minutes. The reaction mixturewas partitioned between EtOAc and 2N K₂CO₃ and brine. The aqueous layerwas extracted with EtOAc (2×). The combined organic layers were driedover MgSO4 and concentrated. The residue was purified by flashchromatography eluting with 5% MeOH/1% NH₄OH in CH₂Cl₂ to afford thetitle compound (19.2 mg, 0.035 mmol, 74.0%). ESI MS m/z 552.3 [M+H]+.

Example 2352-((S)-1-((E)-4-(dimethylamino)but-2-enoyl)-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

Step A.2-((S)-1-((E)-4-(dimethylamino)but-2-enol)-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

To a solution of2-((S)-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile(25 mg, 0.0502 mmol) from Example 234 Step I,(2E)-4-(dimethylamino)but-2-enoic acid (13.0 mg, 0.100 mmol), DIEA (43.9μl, 0.251 mmol) in CH2Cl₂ (502 μl) was added HATU (28.7 mg, 0.0754 mmol)and the resulting mixture was stirred at ambient temperature for 1 hour.The reaction mixture was partitioned between EtOAc and brine. Theaqueous layer was extracted with EtOAc (2×). The combined organic layerswere dried over MgSO4 and concentrated. The residue was purified bypreparative-C18 eluting with 5-95% ACN/H₂O+0.1% TFA. The desiredfractions were partitioned between EA/2M K₂CO₃. The aqueous wasextracted with EtOAc (2×). The combined organic layers were dried overMgSO4 and concentrated to afford the title compound (19.0 mg, 0.031mmol, 62.1%). ESI MS m/z 609.4 [M+H]⁺.

Example 2362-((S)-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-(E-4-(piperidin-1-yl)but-2-enoyl)piperazin-2-yl)acetonitrile

Step A.2-((S)-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-(E-4-(piperidin-1-yl)but-2-enoyl)piperazin-2-yl)acetonitrilewas prepared according to Example 235, substituting(2E)-4-(1-piperidinyl)-2-butenoic acid HCl salt, to afford the titlecompound (30 mg, 0.046 mmol, 92.0%). ESI MS m/z 649.3 [M+H]⁺.

Example 2372-((S)-1-acryloyl-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(2-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile2,2,2-trifluoroacetate

Synthesized according to Example 234 substituting1-bromo-2-(trifluoromethyl)benzene for 1-bromonaphthalene. ES+APCI MSm/z 570.3 [M+H]⁺.

Example 2382-(1-acryloyl-4-(7-(6-methyl-1H-indazol-7-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

Step A:7-bromo-6-methyl-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazole

A solution of 7-bromo-6-methyl-1H-indazole (200 mg, 0.948 mmol) intetrahydrofuran (2 ml, 0.948 mmol) was cooled with stirring in an icebath. Sodium hydride (45.5 mg, 1.14 mmol) was added portionwise to themixture and the reaction was stirred at 0° C. for 1 hour.(2-(chloromethoxy)ethyl)trimethylsilane (0.201 ml, 1.14 mmol) was nextadded and the reaction stirred for 2 hours while warming to roomtemperature. The mixture was divided between EtOAc (20 mL) and water (10mL) and the layers separated. The organic layer was washed with water(2×10 mL), brine (10 mL), dried over Na₂SO₄ and evaporated in vacuo. Theproduct was purified by chromatography on silica gel using 20 to 40%EtOAc/hexanes as eluent to give7-bromo-6-methyl-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazole (46mg, 14%) along with isomer7-bromo-6-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole (214mg, 66%). ES+APCI MS m/z 341.1 [M]⁺.

Step B: Benzyl2-(cyanomethyl)-4-(7-(6-methyl-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-7-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate

A mixture of benzyl2-(cyanomethyl)-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(50 mg, 0.099 mmol),7-bromo-6-methyl-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazole (46mg, 0.13 mmol), Cs₂CO₃ (97 mg, 0.30 mmol), Ruphos Pd G3 (83 mg, 0.099mmol) and dioxane (1 mL) was purged with nitrogen and stirred at 70° C.for 6 hours. The reaction mixture was cooled to room temperature anddivided between EtOAc (20 mL) and water (10 mL) and the layersseparated. The organic layer was washed with water (5 mL), brine (5 mL),dried over Na₂SO₄ and evaporated in vacuo. The product was purified bychromatography on silica gel, Redisep 24 g, using 2 to 20% MeOH/DCM aseluent to give a colorless solid (50 mg, 66%). ES+APCI MS m/z 766.4[M]⁺.

Step C: Benzyl2-(cyanomethyl)-4-(7-(6-methyl-1H-indazol-7-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate

Neat benzyl2-(cyanomethyl)-4-(7-(6-methyl-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-7-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(10 mg, 0.0131 mmol) (10 mg, 0.0131 mmol) was dissolved intrifluoroacetic acid (1 ml, 13.1 mmol) and the yellow-brow solution wasstirred at room temperature for 1.5 hours. The reaction mixture waspoured into ethyl acetate (20 mL) and the organics washed carefully with2M Na₂CO₃ (10 mL, 20 mmol), water (2×3 mL), brine (5 mL), dried overNa₂SO₄ and evaporated in vacuo to give a yellowish solid (8 mg, 96%).ES+APCI MS m/z 636.3 [M+H]⁺.

Step D:2-(1-acrylol-4-(7-(6-methyl-H-indazol-7-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

A stirred mixture of benzyl2-(cyanomethyl)-4-(7-(6-methyl-1H-indazol-7-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(16 mg, 0.02517 mmol), methanol (1.5 ml, 0.02517 mmol), tetrahydrofuran(1.815 mg, 0.02517 mmol) and palladium on carbon (10 mg, 5%, Degussatype E101 NO/W) was degassed and stirred under hydrogen atmosphere for 1hour. The mixture was filtered through Celite (2 mL) and the celitewashed with THE (3×3 mL). The combined organics were concentrated invacuo to −0.5 mL, dissolved in DCM (5 mL), cooled to −30° C. withstirring in an EtOH-H₂O—CO₂ bath. Triethylamine (0.02 mL, 5 eq.) wasnext added followed by acryloyl chloride (0.006134 ml, 0.07550 mmol) andthe reaction mixture was stirred 1 min at −30° C. The reaction wasquenched with NH₄OH (0.03 mL) and concentrated in vacuo. The residue wasdivided between 1M NaHCO₃ (3 mL) and EtOAc (15 mL) and the layersseparated. The organic layer was washed with water (3 mL), brine (3 mL),dried over Na₂SO₄ and evaporated in vacuo. The product was purified bychromatography on silica gel, Redisep 12 g, using 10 to 20%MeOH/DCM+0.2% NH₄OH as eluent to give a colorless solid (5.96 mg, 43%).ES+APCI MS m/z 556.3 [M+H]⁺.

Example 2392-(1-acryloyl-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(3-(trifluoromethyl)pyridin-4-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

Synthesized according to Example 210, Steps E-G using4-Bromo-3-(trifluoromethyl)pyridine hydrobromide in place of1-bromo-2-(trifluoromethyl)benzene in Step E. ES+APCI MS m/z 571.3[M+H]⁺.

Example 2402-(1-acryloyl-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(2-(2,2,2-trifluoroethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

Synthesized according to Example 210, Steps E-G using1-bromo-2-(2,2,2-trifluoroethyl)benzene in place of1-bromo-2-(trifluoromethyl)benzene in Step E. ES+APCI MS m/z 584.3[M+H]⁺.

Example 241 Benzyl2-(cyanomethyl)-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(3-(trifluoromethyl)pyridin-2-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate

Step A: In a vial, benzyl2-(cyanomethyl)-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(100 mg, 0.198 mmol) was dissolved in dioxane (98.9 μl, 0.198 mmol) andtreated with cesium carbonate (129 mg, 0.396 mmol), and2-Fluoro-3-(trifluoromethyl)pyridine (163 mg, 0.989 mmol) The tube wasthen capped and heated to 90° C. for 12 hr. Reaction was filteredthrough GF/F paper and concentrated. The residue was purified by silicachromatography (0-12% MeOH in DCM).

Step B: Synthesized according to Example 210, Steps F-G using benzyl2-(cyanomethyl)-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(3-(trifluoromethyl)pyridin-2-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylatein place of benzyl2-(cyanomethyl)-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(2-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylatein Step F. ES+APCI MS m/z 571.3 [M+H]⁺.

Example 2422-(1-(but-2-ynoyl)-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

At 0° C., to a 25 mL RBF containing N,N-dimethylformamide (603 μL, 0.06mmol) was added2-(4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile(30 mg, 0.06 mmol) and triethylamine (12.2 mg, 0.12 mmol). The reactionmixture was vigorously stirred while 2-Butynoic acid (6.08 mg, 0.07mmol) was added in one portion. Next, 1-Propanephosphonic acid cyclicanhydride (26.9 μl, 0.09 mmol) was added to the stirring mixture. Thereaction was allowed to stir for 2 h at 0° C. Water was added and thereaction extracted with EtOAc (2×25 mL). The organic layers were washedwith saturated LiCl, NaCl, and water (10 mL each wash). Dried andconcentrated to a solid that was purified by reverse phase prep HPLC(5-95% ACN:H₂O, with 0.1% TFA) to provide the title compound.

Example 2432-[4-[2-[[(2R)-1-methylpyrrolidin-2-yl]methoxy]-7-[5-(trifluoromethyl)-1H-indazol-4-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile

Step A: Tert-butyl2-(cyanomethyl)-4-[2-methylsulfanyl-7-[5-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)indazol-4-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate

To a solution of tert-butyl2-(cyanomethyl)-4-(2-methylsulfanyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(1.05 g, 2.60 mmol),2-[[4-bromo-5-(trifluoromethyl)indazol-1-yl]methoxy]ethyl-trimethyl-silane(1.13 g, 2.86 mmol), RuPhos (484 mg, 1.04 mmol) and Cs₂CO₃ (2.11 g, 6.49mmol) in toluene (20 mL) was added Pd₂(dba)₃ (475 mg, 519 umol) underN₂, the suspension was degassed under vacuum and purged with N₂ severaltimes. The mixture was warmed to 90° C. and stirred at 90° C. for 7hours. The reaction mixture was filtered and the filter cake was washedwith EtOAc (3×20 mL). The combined organic layers were concentratedunder vacuum. The residue was purified by silica gel chromatography (PE:EA from 30:1 to 4:1) and then by reversed phase flash column (ACN: 100%)to give tert-butyl2-(cyanomethyl)-4-[2-methylsulfanyl-7-[5-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)indazol-4-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(850 mg, 1.12 mmol, 43.3% yield, 95.0% purity) as a yellow solid. ESI MSm/z 719.5 [M+H]⁺.

Step B: tert-butyl2-(cyanomethyl)-4-[2-methylsulfinyl-7-[5-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)indazol-4-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate

To a solution of tert-butyl2-(cyanomethyl)-4-[2-methylsulfanyl-7-[5-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)indazol-4-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(850 mg, 1.18 mmol) in DCM (17 mL) was added m-CPBA (240 mg, 1.18 mmol,85.0% purity) at 0° C. and stirred at 0° C. for 1 hour. The reactionmixture was quenched by saturated Na₂S₂O₃ (15 mL) at 0° C. andseparated, then diluted with water (10 mL) and extracted with EtOAc (30mL). The combined organic layers were dried over anhydrous Na₂SO₄,filtered and concentrated under vacuum. The residue was purified byreversed phase flash column (ACN/Water (0.1% FA)=80%) to give tert-butyl2-(cyanomethyl)-4-[2-methylsulfinyl-7-[5-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)indazol-4-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(730 mg, 944 umol, 79.8% yield, 95.0% purity) as yellow solid. ESI MSm/z 735.5 [M+H]⁺.

Step C: Tert-butyl2-(cyanomethyl)-4-[2-[[(2R)-1-methylpyrrolidin-2-yl]methoxy]-7-[5-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)indazol-4-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate

To a solution of tert-butyl2-(cyanomethyl)-4-[2-methylsulfinyl-7-[5-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)indazol-4-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(300 mg, 408 umol) and [(2R)-1-methylpyrrolidin-2-yl]methanol (94.0 mg,816 umol) in toluene (6 mL) was added t-BuONa (58.8 mg, 612 umol) at 15°C. and stirred at 15° C. for 0.5 hour. To the mixture was added EtOAc(15 mL) and water (5 mL), then extracted with EtOAc (3×10 mL). Thecombined organic layers were dried over anhydrous Na₂SO₄, filtered andconcentrated under vacuum. The residue was purified by reversed phaseflash column (ACN/Water (0.1% FA)=54%) to give tert-butyl2-(cyanomethyl)-4-[2-[[(2R)-1-methylpyrrolidin-2-yl]methoxy]-7-[5-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)indazol-4-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(216 mg, 261 umol, 64.0% yield, 95.0% purity) as brown solid. ESI MS m/z786.6[M+H]⁺.

Step D:2-[4-[2-[[(2R)-1-methylpyrrolidin-2-yl]methoxy]-7-[5-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)indazol-4-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile

To a solution of tert-butyl2-(cyanomethyl)-4-[2-[[(2R)-1-methylpyrrolidin-2-yl]methoxy]-7-[5-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)indazol-4-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(190 mg, 242 umol) and 2,6-dimethylpyridine (311 mg, 2.90 mmol, 338 uL)in DCM (4 mL) was added TMSOTf (645 mg, 2.90 mmol, 524 uL) at 0° C. andstirred at 20° C. for 1 hour. The reaction mixture was quenched by MeOH(1 mL), then concentrated under vacuum. The residue was purified byreversed phase flash column (ACN/Water (0.1% FA)=40%).2-[4-[2-[[(2R)-1-methylpyrrolidin-2-yl]methoxy]-7-[5-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)indazol-4-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(85 mg, 123 umol, 50.8% yield, 99.0% purity) was obtained as a whitesolid. ESI MS m/z 686.5 [M+H]⁺.

Step E:2-[4-[2-[[(2R)-1-methylpyrrolidin-2-yl]methoxy]-7-[5-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)indazol-4-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile

To a solution of2-[4-[2-[[(2R)-1-methylpyrrolidin-2-yl]methoxy]-7-[5-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)indazol-4-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(85.0 mg, 124 umol), DIEA (96.1 mg, 744 umol, 130 uL) in DCM (2 mL) wasadded prop-2-enoyl prop-2-enoate (23.4 mg, 186 umol) at 0° C. and themixture stirred at 20° C. for 1 hour. The reaction mixture was quenchedby water (2 mL). The resulting mixture was extracted with DCM (3×5 mL).The combined organic layers were dried over anhydrous Na₂SO₄, filteredand concentrated under vacuum The residue was purified by reversed phaseflash column (ACN/Water (0.1% FA)=48%) to give2-[4-[2-[[(2R)-1-methylpyrrolidin-2-yl]methoxy]-7-[5-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)indazol-4-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile(45 mg, 54.7 umol, 44.2% yield, 90.0% purity) as white solid. ¹H NMR(400 MHz, chloroform-d) δ=8.16 (s, 1H), 7.71 (d, J=8.8 Hz, 1H), 7.52 (d,J=8.8 Hz, 1H), 6.59 (br s, 1H), 6.45-6.36 (m, 1H), 5.84 (br d, J=10.4Hz, 1H), 5.76 (s, 2H), 5.12 (s, 1H), 4.44-4.28 (m, 3H), 4.21-4.08 (m,2H), 3.98 (br d, J=12.0 Hz, 1H), 3.63-3.54 (m, 2H), 3.48-3.39 (m, 2H),3.32 (br s, 1H), 3.10 (br s, 2H), 2.99-2.86 (m, 2H), 2.80 (br s, 2H),2.73-2.58 (m, 2H), 2.49 (s, 3H), 2.28 (br s, 1H), 2.05 (br s, 1H), 1.77(br s, 4H), 0.94-0.88 (m, 2H), −0.04 (s, 9H).

Step F:2-[4-[2-[[(2R)-1-methylpyrrolidin-2-yl]methoxy]-7-[5-(trifluoromethyl)-1H-indazol-4-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile

To a solution of2-[4-[2-[[(2R)-1-methylpyrrolidin-2-yl]methoxy]-7-[5-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)indazol-4-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile(45 mg, 60.8 umol) in DCM (0.15 mL) was added TFA (208 mg, 1.82 mmol,135 uL) and the mixture stirred at 20° C. for 1 hour. The reactionmixture was basified by saturated NaHCO₃ (2 mL) to pH=8. The resultingmixture was extracted with DCM:MeOH (10:1) (3×5 mL). The combinedorganic layers were dried over anhydrous Na₂SO₄, filtered andconcentrated under vacuum. The residue was purified by prep-HPLC(column: Phenomenex Synergi C18 150*30 mm*4 um; mobile phase: [water(0.225% FA)-ACN]; B %: 10%-40%, 10.5 min) to give2-[4-[2-[[(2R)-1-methylpyrrolidin-2-yl]methoxy]-7-[5-(trifluoromethyl)-1H-indazol-4-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile(8.2 mg, 12.0 umol, 19.8% yield, 96.2% purity, FA) as yellow oil. ESI MSm/z 610.4 [M+H]⁺.

Example 2442-[4-[7-(8-isoquinolyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile

Step A: tert-butyl2-(cyanomethyl)-4-[7-(8-isoquinolyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate

To a solution of tert-butyl2-(cyanomethyl)-4-[2-[(1-methylpyrrolidin-2-yl)methoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(210 mg, 445 umol), 8-bromoisoquinoline (185 mg, 891 umol), RuPhos (41.6mg, 89.1 umol) and Cs₂CO₃ (435 mg, 1.34 mmol) in toluene (4.5 mL) wasadded Pd₂(dba)₃ (40.8 mg, 44.5 umol) under N₂. The suspension wasdegassed under vacuum and purged with N₂ several times. The mixture wasstirred under N₂ at 90° C. for 12 hours. The mixture was filtered andthe filter cake was washed with EtOAc (3×10 mL). The combined organiclayers were concentrated under vacuum. The residue was purified byreversed phase flash column (ACN/Water (0.1% FA)=20%) to give tert-butyl2-(cyanomethyl)-4-[7-(8-isoquinolyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(160 mg, 240 umol, 54.0% yield, 90.0% purity) as brown solid. ESI MS m/z599.4 [M+H]⁺.

Step B:2-[4-[7-(8-isoquinolyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile

A solution of tert-butyl2-(cyanomethyl)-4-[7-(8-isoquinolyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(190 mg, 317 umol) and TFA (724 mg, 6.35 mmol, 470 uL) was stirred at20° C. for 1 hour. The reaction mixture was concentrated under vacuum togive2-[4-[7-(8-isoquinolyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(230 mg, crude, 2TFA) as a brown oil.

Step C:2-[4-[7-(8-isoquinolyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enol-piperazin-2-yl]acetonitrile

To a solution of2-[4-[7-(8-isoquinolyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(230 mg, 316 umol, 2TFA) and DIEA (409 mg, 3.17 mmol, 551 uL) in DCM (5mL) was added prop-2-enoyl prop-2-enoate (47.9 mg, 380 umol) at 0° C.,then the mixture was stirred at 20° C. for 1 hour. Water (5 mL) wasadded to the mixture. The resulting mixture was extracted with DCM (3×5mL). The combined organic layers were dried over anhydrous Na₂SO₄,filtered and concentrated under vacuum. The residue was purified byprep-HPLC (column: Phenomenex Synergi C18 150*25*10 um; mobile phase:[water (0.225% FA)-ACN]; B %: 1%-20%, 10 min) to give2-[4-[7-(8-isoquinolyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile(12.5 mg, 19.7 umol, 6.23% yield, 94.5% purity, FA) as yellow solid. ESIMS m/z 553.2 [M+H]⁺.

Example 2452-[4-[7-(7-methyl-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile

Step A: (7-methyl-3,4-dihydronaphthalen-1-yl) trifluoromethanesulfonate

To a solution of 7-methyltetralin-1-one (2.00 g, 12.5 mmol) and DIPEA(4.84 g, 37.5 mmol, 6.52 mL) in DCM (30 mL) was added Tf₂O (5.28 g, 18.7mmol, 3.09 mL) dropwise at −5° C. The mixture was stirred at 20° C. for3 hours. Upon completion, the mixture was concentrated under vacuum. Theresidue was purified by silica gel chromatography (PE/EA 1/0 to 100/1)to give (7-methyl-3,4-dihydronaphthalen-1-yl) trifluoromethanesulfonate(1.53 g, 4.45 mmol, 35.6% yield, 85.0% purity) as a yellow oil. ¹H NMR(400 MHz, chloroform-d) δ=7.17 (s, 1H), 7.11-7.05 (m, 2H), 6.01 (t,J=4.8 Hz, 1H), 2.83 (t, J=8.0 Hz, 2H), 2.50 (dt, J=4.8, 8.0 Hz, 2H),2.36 (s, 3H).

Step B: (7-methyl-1-naphthyl) trifluoromethanesulfonate

A mixture of (7-methyl-3,4-dihydronaphthalen-1-yl)trifluoromethanesulfonate (1.40 g, 4.79 mmol) and DDQ (2.17 g, 9.58 mmol) indioxane (28 mL) was stirred at 105° C. for 12 hours. Upon completion,the mixture was concentrated under vacuum. The residue was purified bysilica gel chromatography (PE/EA 1/0 to 100/1) to give(7-methyl-1-naphthyl) trifluoromethanesulfonate (1.10 g, 3.41 mmol,71.2% yield, 90.0% purity) as a yellow oil. ¹H NMR (400 MHz,chloroform-d) 6=7.87-7.79 (m, 3H), 7.49-7.38 (m, 3H), 2.59 (s, 3H).

Step C: tert-butyl4-(7-benzyl-2-chloro-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate

A mixture of 7-benzyl-2,4-dichloro-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine (10 g, 34.0 mmol), 2-piperazin-2-ylacetonitrile (10.1g, 51.0 mmol, 2 HCl) and DIEA (17.6 g, 136 mmol, 23.7 mL) in dioxane(100 mL) was stirred at 50° C. for 2 hours. Boc₂O (14.8 g, 68.0 mmol,15.6 mL) was added and the mixture was stirred at 50° C. for 2 hours.The mixture was concentrated under vacuum and the residue was dilutedwith ethyl acetate (500 mL). The separated organic layer was washed withwater (1×300 mL), brine (1×200 mL), dried over sodium sulfate, filteredand concentrated under vacuum. The residue was triturated with ethylacetate (100 mL). The precipitate was filtered and the filtered cake waswashed with ethyl acetate (50 mL) and dried under vacuum to give a graysolid. The filtrate was concentrated under vacuum. The residue waspurified by column chromatography over silica gel (petroleum ether/ethylacetate 100/1 to 1/2). The desired fractions were collected andconcentrated under vacuum to give solid then combined with above solidto give tert-butyl 4-(7-benzyl-2-chloro-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate (15 g, 29.10mmol, 85.6% yield, 93.7% purity) as yellow solid. ESI MS m/z 483.1[M+H]⁺.

Step D:4-[7-benzyl-2-[(1-methylpyrrolidin-2-yl)methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(cyanomethyl)piperazine-1-carboxylate

To a solution of [(2S)-1-methylpyrrolidin-2-yl]methanol (1.19 g, 10.4mmol, 1.23 mL, 2.5 eq) in THE (30.0 mL) was added NaH (331 mg, 8.28mmol, 60% purity in mineral oil, 2.00 eq) at 0° C. and the mixture wasstirred at 0° C. for 0.5 h. tert-Butyl4-(7-benzyl-2-chloro-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate(2.00 g, 4.14 mmol, 1.00 eq) was added into the mixture and the mixturewas stirred at 80° C. for 4 hours. The mixture was poured into ice water(100 mL) and extracted with ether acetate (3×150 mL). The organic layerswere washed with saturated sodium chloride solution (1×200 mL), driedover Na₂SO₄, filtered and concentrated under vacuum to give tert-butyl4-[7-benzyl-2-[(1-methylpyrrolidin-2-yl)methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(cyanomethyl)piperazine-1-carboxylate (2.86 g, crude)as a black oil which was used in the next step without furtherpurification. ESI MS m/z 562.3 [M+H]⁺.

Step E: tert-butyl2-(cyanomethyl)-4-[2-[(1-methylpyrrolidin-2-yl)methoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate

NH₃ was bubbled into methanol (70.0 mL) at −78° C. for 30 minutes.tert-Butyl4-[7-benzyl-2-[(1-methylpyrrolidin-2-yl)methoxy]-6,8-dihydro-5H-pyrido[3,4-d] pyrimidin-4-yl]-2-(cyanomethyl)piperazine-1-carboxylate (2.00 g,crude) and Pd/C (0.20 g, 10% purity) were added into the mixture. Themixture was stirred at 40° C. for 24 hours under H₂ at 15 psi. Themixture was filtered and concentrated under vacuum. The residue waspurified by reverse phase flash [water (FA, 0.1%)/ancetonitrile]. Thedesired fractions were adjusted to pH >7 by saturated sodium bicarbonatesolution (5.00 mL) and the aqueous layer extracted with ether acetate(3×100 mL). The combined organic layers were washed with brine (1×100mL), dried over Na₂SO₄, filtered and concentrated under vacuum to givetert-butyl2-(cyanomethyl)-4-[2-[(1-methylpyrrolidin-2-yl)methoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(0.40 g, 845 umol, two steps 29.4% yield) as a yellow solid. ESI MS m/z472.2 [M+H]⁺.

Step F: tert-butyl2-(cyanomethyl)-4-[2-[(1-methylpyrrolidin-2-yl)methoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate

A solution of tert-butyl2-(cyanomethyl)-4-[2-[(1-methylpyrrolidin-2-yl)methoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(185 mg, 392 umol), (7-methyl-1-naphthyl) trifluoromethanesulfonate (159mg, 549 umol), Pd₂(dba)₃ (35.9 mg, 39.2 umol), RuPhos (36.6 mg, 78.5umol) and Cs₂CO₃ (320 mg, 981 umol) in toluene (30 mL) was de-gassedwith N₂ and then heated to 90° C. for 12 hours under N₂. Uponcompletion, the mixture was filtered and the filtrate was concentratedunder vacuum. The residue was purified by reversed-phase flash [water(0.1% NH₃.H₂)/acetonitrile] to give tert-butyl2-(cyanomethyl)-4-[7-(7-methyl-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(180 mg, 283 umol, 72.1% yield, 96.1% purity) as a yellow solid. ESI MSm/z 612.6 [M+H]⁺.

Step G:2-[4-[7-(7-methyl-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile

A solution of tert-butyl2-(cyanomethyl)-4-[7-(7-methyl-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(180 mg, 294 umol) in TFA (671 mg, 5.88 mmol, 436 uL) was stirred at 20°C. for 1 hour. Upon completion the mixture was concentrated under vacuumto give2-[4-[7-(7-methyl-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(0.37 g, crude, TFA) as a yellow oil which was used directly in the nextstep without further purification.

Step H:2-[4-[7-(7-methyl-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile

To a solution of 2-[4-[7-(7-methyl-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(189 mg, crude, TFA) and DIEA (976 mg, 7.55 mmol, 1.32 mL) in DCM (4 mL)was added prop-2-enoyl prop-2-enoate (38.1 mg, 302 umol) dropwise at 0°C. The mixture was stirred at 25° C. for 1 hour. Upon completion, thereaction was quenched with MeOH (0.5 mL), diluted with water (1 mL) andextracted with DCM (3×5 mL). The organic layers were dried over Na₂SO₄and concentrated under vacuum. The residue was purified by prep-HPLC(column: Phenomenex Synergi C18 150*30 mm*4 um; mobile phase: [water(0.225% FA)-ACN]; B %: 15%-45%, 10.5 min) to give2-[4-[7-(7-methyl-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile(13.2 mg, 21.3 umol, two steps 14.2% yield, 98.4% purity, FA) as ayellow solid. ESI MS m/z 566.5 [M+H]⁺.

Example 2462-[4-[7-(4-fluoro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile

Synthesized according to the method for Example 147 substituting1-bromo-4-fluoronaphthalene for 1-bromonaphthalene in step H. ESI MS m/z570.5 [M+H]⁺.

Example 2472-(1-acryloyl-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(quinolin-8-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

Synthesized according to the method for Example 147 substituting8-bromoquinoline for 1-bromonaphthalene in Step H. ESI MS m/z 553.2[M+H]⁺.

Example 248(S)-1-(4-(7-(5-isopropyl-1H-indazol-4-yl)-2-((1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Step A: 2-(2-bromo-4-fluoro-phenyl)propan-2-ol

To a solution of 1-(2-bromo-4-fluoro-phenyl)ethanone (10 g, 46.1 mmol)in THF (100 mL) was added MeMgBr (in ether) (3 M, 46.08 mL) at −50° C.The mixture was warmed up to 0° C. and stirred for 3 hours. The mixturewas quenched with saturated aqueous ammonium chloride solution (10 mL)at −50° C. The mixture was warmed up to 15° C. and was then diluted withethyl acetate (500 mL). The separated organic layer was washed withwater (1×500 mL) and brine (1×500 mL), dried over sodium sulfate,filtered and concentrated under vacuum to give2-(2-bromo-4-fluoro-phenyl)propan-2-ol (10 g, 36.5 mmol, 79.2% yield,85% purity) as a colorless oil.

Step B: 2-bromo-4-fluoro-1-isopropyl-benzene

To a solution of 2-(2-bromo-4-fluoro-phenyl)propan-2-ol (9 g, 38.6 mmol)in dichloromethane (100 mL) was added Et₃SiH (8.98 g, 77.2 mmol, 12.3mL) and TFA (65.1 g, 571 mmol, 42.3 mL). The mixture was stirred at 15°C. for 1 hour and then heated to 50° C. for 1 hour. The reaction mixturewas concentrated under vacuum and then diluted with ethyl acetate (100mL). The aqueous layer pH was adjusted to pH=7 by addition of saturatedNaHCO₃ aqueous solution and extracted with ethyl acetate (50 mL×3). Thecombined organic phase was washed with brine (30 mL), dried withanhydrous Na₂SO₄, filtered and concentrated under vacuum. The residuewas purified by silica gel chromatography (Petroleum ether/Ethylacetate=1/0 to 100/1). The desired fractions were collected andconcentrated under vacuum. 2-bromo-4-fluoro-1-isopropyl-benzene (7 g,32.2 mmol, 83.5% yield) was obtained as colorless oil. ¹H NMR (400 MHz,chloroform-d) δ=7.36-7.27 (m, 2H), 7.09-7.02 (m, 1H), 3.46-3.31 (m, 1H),1.28 (d, J=6.8 Hz, 6H).

Step C: 2-bromo-6-fluoro-3-isopropyl-benzaldehyde

To a mixture of 2-bromo-4-fluoro-1-isopropyl-benzene (7 g, 32.2 mmol inTHE (100 mL) was added LDA (2 M in toluene, 24.2 mL) at −70° C. undernitrogen atmosphere. The mixture was stirred for 0.5 hour, and then DMF(7.07 g, 96.7 mmol, 7.44 mL) was added. The mixture was stirred at −70°C. for 2 hours. The reaction was quenched with water (100 mL) andextracted with ethyl acetate (2×100 mL). The combined organic layerswere washed with brine (50 mL), dried over Na₂SO₄, filtered andconcentrated under reduced pressure. The residue was purified by columnchromatography (SiO2, PE\EA=1\0 to 10\1). The desired fractions werecollected and concentrated under vacuum to give2-bromo-6-fluoro-3-isopropyl-benzaldehyde (2.4 g, 9.79 mmol, 30.4%yield) as a yellow oil. ¹H NMR (400 MHz, chloroform-d) δ=10.41 (s, 1H),7.48 (dd, J=5.6, 8.8 Hz, 1H), 7.13 (t, J=9.2, 1H), 3.57-3.46 (m, 1H),1.26 (d, J=7.2 Hz, 6H).

Step D: 4-bromo-5-isopropyl-1H-indazole

2-bromo-6-fluoro-3-isopropyl-benzaldehyde (2.4 g, 9.79 mmol) in DMSO (3mL) was added N₂H₄.H₂O (15.4 g, 302 mmol, 15 mL, 98% purity) and themixture was heated to 110° C. and stirred for 16 hours. The reactionmixture was poured into H₂O (10 mL) and extracted with ethyl acetate (20mL×3). The organic phase was washed with brine (10 mL), dried overanhydrous Na₂SO₄ and concentrated under vacuum to give the residue. Theresidue was purified by column chromatography (SiO₂, Petroleumether/Ethyl acetate=1/0 to 5/1) to give 4-bromo-5-isopropyl-1H-indazole(650 mg, 2.72 mmol, 27.8% yield) as a yellow solid. ¹H NMR (400 MHz,chloroform-d) δ=10.24 (br s, 1H), 8.08 (d, J=0.8 Hz, 1H), 7.43 (d, J=8.8Hz, 1H), 7.34 (d, J=8.8 Hz, 1H), 3.56 (td, J=6.8, 13.6 Hz, 1H), 1.29 (d,J=6.8 Hz, 6H).

Step E: 4-bromo-5-isopropyl-1-tetrahydropyran-2-yl-indazole

To a solution of 3,4-dihydro-2H-pyran (457 mg, 5.44 mmol, 497 uL, 2 eq)in dichloromethane (15 mL) was added TsOH.H₂O (51.7 mg, 271 umol) and4-bromo-5-isopropyl-1H-indazole (650 mg, 2.72 mmol). The mixture wasstirred at 20° C. for 3 hours. The reaction mixture was diluted withwater (20 mL) and extracted with ethyl acetate (20 mL×2). The combinedorganic layers were washed with brine (20 mL), dried over Na₂SO₄,filtered and concentrated under reduced pressure to give a residue. Theresidue was purified by column chromatography (SiO₂, Petroleumether/Ethyl acetate=1/0 to 5/1) and further purificated by reversedphase flash [water (0.1% formic acid)/acetonitrile] to give4-bromo-5-isopropyl-1-tetrahydropyran-2-yl-indazole (170 mg, 494 umol,18.2% yield, 94% purity) as a yellow oil. ESI MS m/z 323.0 [M+H]⁺.

Step F: tert-butyl4-[7-(5-isopropyl-1-tetrahydropyran-2-yl-indazol-4-yl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate

A mixture of 4-bromo-5-isopropyl-1-tetrahydropyran-2-yl-indazole (136mg, 420 umol), tert-butyl4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(140 mg, 323 umol), RuPhos (15.1 mg, 32.4 umol), RuPhos-Pd-G2 (25.1 mg,32.4 umol) and t-BuONa (77.7 mg, 809 umol) in toluene (3 mL) wasdegassed and purged with N₂ 3 times and the mixture was stirred at 90°C. for 12 hours under N₂ atmosphere. The mixture was diluted with ethylacetate (20 mL) and washed with water (20 mL). The organic layers werewashed with brine (10 mL), dried over Na₂SO₄, filtered and concentratedunder reduced pressure to give a residue. The residue was purified bycolumn chromatography (SiO₂, DCM/MeOH=100/1 to 10/1) and the desiredfractions were collected and concentrated under vacuum to givetert-butyl4-[7-(5-isopropyl-1-tetrahydropyran-2-yl-indazol-4-yl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(70 mg, 96.5 umol, 29.8% yield, 93% purity) was as a yellow solid. ESIMS m/z 675.3 [M+H]⁺.

Step G:7-(5-isopropyl-H-indazol-4-yl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-4-piperazin-1-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine

To a solution of tert-butyl4-[7-(5-isopropyl-1-tetrahydropyran-2-yl-indazol-4-yl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(40 mg, 59.3 umol) in dichloromethane (100 uL) was added TFA (101 mg,889 umol, 65.8 uL). The mixture was stirred at 25° C. for 1 hour. Themixture was concentrated under vacuum to give7-(5-isopropyl-1H-indazol-4-yl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-4-piperazin-1-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine(42 mg, 58.4 umol, 98.6% yield, 2 TFA) as a brown oil which was used innext step directly without purification. ESI MS m/z 491.4 [M+H]⁺.

Step H:1-[4-[7-(5-isopropyl-H-indazol-4-yl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one

To a mixture of7-(5-isopropyl-1H-indazol-4-yl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-4-piperazin-1-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine(42 mg, 58.4 umol) and DIEA (75.5 mg, 584 umol, 102 uL) indichloromethane (2 mL) was added a solution of prop-2-enoylprop-2-enoate (7.37 mg, 58.4 umol, 1 eq) in dichloromethane (1 mL) at−40° C. under nitrogen atmosphere. The mixture was stirred at −40° C.for 1 hour. The reaction was quenched by adding saturated NaHCO₃ (2 mL)aqueous solution. Then the mixture was poured into water (20 mL) andextracted with dichloromethane (20 mL×2). The combined organics weredried over sodium sulfate, filtered and concentrated in vacuo. Theresidue was purified by prep-HPLC (column: Luna C18 150*25 5u; mobilephase: [water (0.225% FA)-ACN]; B %: 5%-38%, 10 min) to give1-[4-[7-(5-isopropyl-1H-indazol-4-yl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one(4.5 mg, 7.93 umol, 13.6% yield, 96% purity) as a yellow solid. ESI MSm/z 545.2 [M+H]⁺.

Example 2491-[4-[7-(2-fluoro-3-hydroxy-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one

Step A: tert-butyl4-[7-(2-fluoro-3-methoxy-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate

A mixture of tert-butyl4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(0.50 g, 1.16 mmol), (2-fluoro-3-methoxy-1-naphthyl)trifluoromethanesulfonate (562 mg, 1.73 mmol), RuPhos (108 mg, 231umol), Pd₂(dba)₃ (106 mg, 116 umol) and t-BuONa (333 mg, 3.47 mmol) intoluene (7 mL) was stirred at 110° C. for 3 hours under nitrogenatmosphere. The mixture was cooled and the pH of the aqueous layeradjusted to 7 by addition of saturated sodium bicarbonate solution andthe aqueous layer extracted with ether acetate (3×20 mL). The combinedorganic layers were washed with saturated sodium chloride solution,dried over Na₂SO₄, filtered and concentrated under vacuum. The residuewas purified by column chromatography (SiO₂,dichloromethane/methanol=10/1) and the mixture was concentrated to givetert-butyl4-[7-(2-fluoro-3-methoxy-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(0.20 g, 274 umol, 11.8% yield) as a yellow solid. ESI MS m/z 607.0[M+H]⁺.

Step B:7-(2-fluoro-3-methoxy-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-4-piperazin-1-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine

A mixture tert-butyl4-[7-(2-fluoro-3-methoxy-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(0.20 g, 330 umol) and TFA (564 mg, 4.94 mmol, 366 uL) indichloromethane (0.4 mL) was stirred at 10° C. for 1 hour. The mixturewas concentrated under vacuum to give7-(2-fluoro-3-methoxy-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-4-piperazin-1-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine (205mg, crude) as a yellow oil which was used in the next step withoutfurther purification. ESI MS m/z 507.0 [M+H]⁺.

Step C:1-[4-[7-(2-fluoro-3-methoxy-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one

To a solution of 7-(2-fluoro-3-methoxy-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-4-piperazin-1-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine(0.20 g, crude) and TEA (399 mg, 3.95 mmol, 549 uL) in dichloromethane(5 mL) was added prop-2-enoyl prop-2-enoate (49.8 mg, 394 umol) at −40°C., then stirred at −40° C. for 0.5 h. The mixture was quenched withmethanol (0.10 mL) and concentrated under vacuum. The residue waspurified by reversed phase flash [water (0.1% TFA)/acetonitrile]. Theaqueous layer pH was to 7 by addition of saturated sodium bicarbonatesolution and the aqueous layer extracted with dichloromethane/methanol(10/1) (3×10 mL). The combined organic layers were washed with saturatedsodium chloride (1×5 mL), dried over Na₂SO₄, filtered and concentratedunder vacuum to give1-[4-[7-(2-fluoro-3-methoxy-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one(0.10 g, 174 umol, 44.1% yield) as a yellow oil. ESI MS m/z 561.5[M+H]⁺.

Step D:1-[4-[7-(2-fluoro-3-hydroxy-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one

To a solution of1-[4-[7-(2-fluoro-3-methoxy-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one(0.10 g, 174 umol) in dichloromethane (3 mL) was added BBr₃ (223 mg, 892umol, 85.9 uL) at −78° C. The mixture was stirred at −78° C. for 0.5 hand 0° C. for 2 hours. The mixture was concentrated under vacuum,diluted with dichloromethane (3 mL) and water and the aqueous layer pHadjusted to >7 by addition of saturated sodium bicarbonate solution at−78-0° C. The aqueous layer was next extracted with dichloromethane(3×5.00 mL). The combined organics were concentrated under vacuum. Theresidue was purified by column chromatography (Al₂O₃,dichloromethane/methanol=10/1) and the mixture was concentrated undervacuum. The residue was purified by prep-HPLC (column: Phenomenex Gemini150*25 mm*10 um; mobile phase: [water (10 mM NH₄HCO₃)-ACN]; B %:30%-60%, 3 min) and further purified by prep-HPLC (column: Luna C18150*25 5u; mobile phase: [water (0.225% FA)-ACN]; B %: 20%-50%, 10 min).The desired fractions were collected and lyophilized to give1-[4-[7-(2-fluoro-3-hydroxy-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one(1.59 mg, 2.91 umol, 1.63% yield, 100% purity, FA) as a yellow solid.ESI MS m/z 547.2[M+H]⁺.

Example 250

1-[4-[7-(5-chloro-1H-indazol-4-yl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one

Step A: 4-bromo-5-chloro-1-tetrahydropyran-2-yl-indazole

To a solution of 4-bromo-5-chloro-1H-indazole (100 mg, 432.0 umol) inDCM (3 mL) was added TsOH H₂O (8.22 mg, 43.2 umol) and3,4-dihydro-2H-pyran (72.7 mg, 864 umol, 79.0 uL). The mixture wasstirred at 20° C. for 2 hours. The reaction was washed by water (20 mL)and the aqueous layer extracted with ethyl acetate (20 mL×2). Thecombined organics were dried with Na₂SO₄ and the solvent removed undervacuum. The residue was purified by column chromatography (SiO₂,Petroleum ether/Ethyl acetate=10:1) to give4-bromo-5-chloro-1-tetrahydropyran-2-yl-indazole (270 mg, 810 umol,93.8% yield) as a white solid. ESI MS m/z 547.2[M+H]⁺.

Step B:tert-butyl-4-[7-(5-chloro-1-tetrahydropran-2-yl-indazol-4-yl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate

A mixture of tert-butyl4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(123 mg, 284.4 umol), 4-bromo-5-chloro-1-tetrahydropyran-2-yl-indazole(135 mg, 427 umol), Pd₂(dba)₃ (26.0 mg, 28.4 umol), RuPhos (20.0 mg,42.9 umol) and Cs₂CO₃ (278 mg, 853 umol) in dioxane (10 mL) was degassedand purged with N₂ and then the mixture was stirred at 100° C. for 12hrs under N₂ atmosphere. The reaction was quenched by adding water (20mL). The mixture was extracted with ethyl acetate (20 mL×3). Thecombined organics were dried with Na₂SO₄ and the solvent wasconcentrated under vacuum. The residue was purified by columnchromatography (SiO₂, Ethyl acetate/MeOH=10/1) to givetert-butyl-4-[7-(5-chloro-1-tetrahydropyran-2-yl-indazol-4-yl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(130.0 mg, 188.4 umol, 66.3% yield) as a white solid. ESI MS m/z668.2[M+H]⁺.

Step C:7-(5-chloro-H-indazol-4-yl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-4-piperazin-1-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine

To a solution of tert-butyl4-[7-(5-chloro-1-tetrahydropyran-2-yl-indazol-4-yl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(50.0 mg, 74.9 umol) in DCM (2 mL) was added TFA (1.95 mL). The mixturewas stirred at 20° C. for 1 hr. The organic solvent was removed undervacuum to give7-(5-chloro-1H-indazol-4-yl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-4-piperazin-1-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine(40.0 mg, crude, 2TFA) as a yellow oil which was used directly in thenext step without further purification. ESI MS m/z 483.4[M+H]⁺.

Step D:1-[4-[7-(5-chloro-H-indazol-4-yl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one

To a solution of7-(5-chloro-1H-indazol-4-yl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-4-piperazin-1-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine(40.0 mg, 2TFA) and DIEA (50 mg, 387 umol, 67.4 uL) in DCM (3 mL) wasadded dropwise acrylic anhydride (9.0 mg, 71.4 umol) under N₂atmosphere. The mixture was stirred at −70° C. for 15 mins. The reactionwas quenched by adding water (10 mL). The mixture was extracted withethyl acetate (10 mL×3). The organic layer was dried with Na₂SO₄ and thesolvent removed under vacuum. The residue was purified by prep-HPLC(column: Luna C18 150*25 5u; mobile phase: [water (0.225% FA)-ACN]; B %:10%-37%, 10 mins) and lyophilized to give1-[4-[7-(5-chloro-1H-indazol-4-yl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one(11.9 mg, 20.8 umol, two steps 27.3%, 100% e.e.) as a yellow solid. ESIMS m/z 537.2 [M+H]⁺.

Example 251

2-(1-acryloyl-4-(2-(((S)-1,2-dimethylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

Step A: Benzyl4-(2-(((S)-1-(tert-butoxycarbonyl)-2-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate

In a microwave tube benzyl4-(2-chloro-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate(200 mg, 0.362 mmol) was dissolved in dioxane (181 μl, 0.362 mmol) andtreated with cesium carbonate (236 mg, 0.723 mmol) and (S)-tert-butyl2-(hydroxymethyl)-2-methylpyrrolidine-1-carboxylate (389 mg, 1.81 mmol).The tube was then capped and heated to 90° C. for 2 hours. LC/MS showedreaction completion. The reaction was cooled to room temperature andfiltered through GF/F paper. The filtrate was concentrated in vacuo andchromatographed on the CombiFlash (0%-10% DCM:MeOH). All fractionscontaining clean product were combined and concentrated to give benzyl4-(2-(((S)-1-(tert-butoxycarbonyl)-2-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate(264 mg, 0.361 mmol, 99.7% yield). ES+APCI MS m/z 732.4 [M+H]⁺.

Step B: benzyl2-(cyanomethyl)-4-(2-(((S)-2-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate

benzyl4-(2-(((S)-1-(tert-butoxycarbonyl)-2-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate(264 mg, 0.361 mmol) was dissolved in dichloromethane (3607 μl, 0.361mmol) and treated with TFA (556 μl, 7.21 mmol). The reaction stirred atroom temperature for 1 hour. LC/MS showed reaction completion. Thereaction was concentrated in vacuo and treated with saturated bicarb.The aqueous layer was extracted with DCM (2×) and the combined organicsdried over Na2SO4 and concentrated in vacuo to give benzyl2-(cyanomethyl)-4-(2-(((S)-2-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(210 mg, 0.332 mmol, 92.2% yield). ES+APCI MS m/z 632.3 [M+H]⁺.

Step C: Benzyl2-(cyanomethyl)-4-(2-(((S)-1,2-dimethylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate

benzyl2-(cyanomethyl)-4-(2-(((S)-2-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(105 mg, 0.1662 mmol) was dissolved in formic acid (94.05 μl, 2.493mmol) and treated with Formaldehyde (1868 μl, 24.93 mmol). The reactionmixture stirred at 85° C. for 1 hour. LC/MS showed reaction completion.The reaction was cooled to room temperature and treated with saturatedbicarb and the mixture was extracted with DCM (2×) and the organicscombined and dried over Na₂SO₄. The combined organics were concentratedin vacuo and chromatographed on the CombiFlash (0%-10% DCM:MeOH). Allfractions containing clean product were combined and concentrated invacuo to give benzyl2-(cyanomethyl)-4-(2-(((S)-1,2-dimethylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(75 mg, 0.1161 mmol, 69.88% yield). ES+APCI MS m/z 646.4 [M+H]⁺.

Step D:2-(4-(2-(((S)-1,2-dimethylpyrrolidin-2-ylmethoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-ylacetonitrile

A solution of benzyl2-(cyanomethyl)-4-(2-(((S)-1,2-dimethylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(117 mg, 0.181 mmol) in EtOH (1812 μl, 0.181 mmol) and THF (1812 μl,0.181 mmol) was purged with N₂ for 5 minutes. To this solution was addedPalladium (96.4 mg, 0.0453 mmol) (Degussa Type, 10 wt %, 50% H₂O), andwas immediately capped and purged with N₂ for an additional 5 min. Thesolution was then stirred under H₂ atmosphere for 1 hour. LC/MS showedclean desired product. The mixture was diluted with MeOH and filteredthrough packed celite. The filtrate was then concentrated in vacuo toprovide2-(4-(2-(((S)-1,2-dimethylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile(88 mg, 0.172 mmol, 94.9% yield). ES+APCI MS m/z 512.3 [M+H]⁺.

Step E:2-(1-acryloyl-4-(2-(((S)-1,2-dimethylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

To a suspension of2-(4-(2-(((S)-1,2-dimethylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile(88 mg, 0.17 mmol) in dichloromethane (1720 μl, 0.17 mmol) at ambienttemperature was added Acyloyl Chloride (14 μl, 0.17 mmol) followed byHunig's base (60 μl, 0.34 mmol). The reaction was then stirred atambient temperature for 30 minutes. LC/MS showed reaction completion.The reaction mixture was concentrated in vacuo. The concentrate wasresuspended in a 60:40 mixture of ACN:H₂O and purified on the Gilson(prep HPLC) using 5->95% ACN/0.1% TFA in water/0.1% TFA as eluent.Fractions containing product were combined and free based with saturatedbicarb and the organics extracted with DCM. The organics were dried overMgSO4 and concentrated in vacuo to give2-(1-acryloyl-4-(2-(((S)-1,2-dimethylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile(14 mg, 0.025 mmol, 14% yield). ES+APCI MS m/z 566.3 [M+H]⁺.

Example 252 Tert-butyl2-(cyanomethyl)-4-[2-[[(2S)-1-isopropylpyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate

Step A: (S)-pyrrolidin-2-ylmethanol

To a solution of (S)-tert-butyl 2-(hydroxymethyl)pyrrolidine-1-carboxylate (2 g, 9.94 mmol) in CH₂Cl₂ (40 mL) was addedHCl (4 M in dioxane, 49.69 mL) at 0° C. under a nitrogen atmosphere.After stirring at 15° C. for 30 min, the mixture was concentrated undervacuum. (S)-pyrrolidin-2-ylmethanol (1.37 g, 9.96 mmol, 100% yield, HCl)was obtained as a yellow solid.

Step B: [(2)-1-isopropylpyrrolidin-2-yl] methanol

A mixture of [(2S)-pyrrolidin-2-yl]methanol (750 mg, 7.41 mmol, 724 uL)and acetone (4.31 g, 74.2 mmol, 5.46 mL) in MeOH (20 mL) washydrogenated under H₂ (30 psi) with Pd/C (100 mg, 7.41 mmol, 10% purity)at 15° C. for 3 hours. The mixture was filtered and concentrated undervacuum. [(2S)-1-isopropylpyrrolidin-2-yl]methanol (0.821 g, 5.73 mmol,77.3% yield) was obtained as a yellow oil. ¹H NMR (400 MHz, methanol-d₄)δ=3.54 (dd, J=4.0, 10.8 Hz, 1H), 3.40-3.35 (m, 1H), 2.99-2.86 (m, 3H),2.60-2.50 (m, 1H), 1.94-1.82 (m, 1H), 1.82-1.66 (m, 3H), 1.15 (d, J=6.4Hz, 3H), 1.08 (d, J=6.4 Hz, 3H).

Step C: Tert-butyl2-(cyanomethyl)-4-[2-[[(2S)-1-isopropylpyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate

To a mixture of tert-butyl2-(cyanomethyl)-4-[2-methylsulfinyl-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(300 mg, 549 umol) and [(2S)-1-isopropylpyrrolidin-2-yl]methanol (157mg, 1.10 mmol) in THF (5 mL) was added t-BuONa (158 mg, 1.65 mmol).After stirring at 20° C. for 0.5 hour, the reaction mixture wasneutralized with HCl (1 M) to pH=7 while holding the solutiontemperature to 0° C., and then the mixture was concentrated underreduced pressure. The residue was purified by reversed phase flash[water (0.1% TFA)/acetonitrile]. The desired fractions were collectedand neutralized with saturated NaHCO₃ solution and extracted with ethylacetate (200 mL). The organic layer was dried over sodium sulfate,filtered and concentrated under vacuum. tert-butyl2-(cyanomethyl)-4-[2-[[(2S)-1-isopropylpyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(174 mg, 278 umol, 50.7% yield, 100% purity) was obtained as a yellowoil. ESI MS m/z 626.2 [M+H]⁺.

Step D: 2-[4-[2-[[(2S)-1-isopropylpyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile

To a solution of tert-butyl 2-(cyanomethyl)-4-[2-[[(2S)-1-isopropylpyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate(174 mg, 278 umol) in CH2C2 (5 mL) was added TFA (7.70 g, 67.5 mmol,5.00 mL) at 0° C. under nitrogen atmosphere. After stirring at 15° C.for 0.5 h, the mixture was concentrated under vacuum.2-[4-[2-[[(2S)-1-isopropylpyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(178 mg, crude, TFA) was obtained as a yellow oil. ESI MS m/z 526.1[M+H]⁺.

Step E:2-[4-[2-[[(2S)-1-isopropylpyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile

To a mixture of2-[4-[2-[[(2S)-1-isopropylpyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile(178 mg, crude, TFA salt) and DIEA (360 mg, 2.78 mmol, 485 uL) in CH2C2(5 mL) was added prop-2-enoyl prop-2-enoate (28.1 mg, 223 umol) at 0° C.The mixture was stirred at 20° C. for 1 hour. The reaction mixture wasquenched with NaHCO₃ saturated solution (5 mL) at 0° C., and thenextracted with CH₂Cl₂ (2×25 mL). The combined organic layers were washedwith brine (1×50 mL), dried over sodium sulfate, filtered andconcentrated under vacuum. The residue was purified by prep-HPLC(column: Boston Green ODS 150*30 5u; mobile phase: [water (0.225%FA)-ACN]; B %: 27%-54%, 10 min).2-[4-[2-[[(2S)-1-isopropylpyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile(11.7 mg, 18.3 umol, two steps 6.58% yield, 97.9% purity, FA) wasobtained as a brown solid. ESI MS m/z 580.2 [M+H]⁺.

Example 2532-(1-acryloyl-4-(7-(7-chloronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

Step A: (7-chloro-3,4-dihydronaphthalen-1-yl) trifluoromethanesulfonate

To a mixture of 7-chlorotetralin-1-one (2 g, 11.1 mmol, 1 eq) and DIEA(4.29 g, 33.2 mmol, 5.79 mL) in DCM (35 mL) was added Tf₂O (4.69 g, 16.6mmol, 2.74 mL) in one portion at 0° C. under N₂. The mixture was stirredat 25° C. for 5 hours. The reaction mixture was concentrated underreduced pressure. The residue was purified by column chromatography(SiO₂, Petroleum ether/Ethyl acetate=200/1 to 50/1).(7-chloro-3,4-dihydronaphthalen-1-yl) trifluoromethanesulfonate (2.25 g,7.02 mmol, 63.4% yield, 97.6% purity) was obtained as a colorless oil.¹H NMR (400 MHz, chloroform-d) δ=7.32 (d, J=2.0 Hz, 1H), 7.24 (dd,J=2.0, 8.0 Hz, 1H), 7.12 (d, J=8.0 Hz, 1H), 6.10 (t, J=4.8 Hz, 1H),2.88-2.80 (m, 2H), 2.53 (dt, J=4.8, 8.0 Hz, 2H).

Step B: (7-chloro-1-naphthyl) trifluoromethanesulfonate

To a mixture of (7-chloro-3,4-dihydronaphthalen-1-yl)trifluoromethanesulfonate (1.57 g, 5.02 mmol) in dioxane (35 mL) wasadded DDQ (2.28 g, 10.0 mmol) in one portion under N₂. The mixture wasstirred at 25° C. for 30 min, then heated to 105° C. and stirred for 5hours. The reaction mixture was concentrated under reduced pressure toremove 1,4-dioxane. The residue was purified by column chromatography(SiO₂, Petroleum ether/Ethyl acetate=200/1 to 50/1).(7-chloro-1-naphthyl) trifluoromethanesulfonate (1.24 g, 3.94 mmol,78.5% yield, 98.7% purity) was obtained as a colorless oil. ¹H NMR (400MHz, chloroform-d) 6=8.05 (d, J=2.0 Hz, 1H), 7.87-7.83 (m, 2H),7.57-7.47 (m, 3H).

Title compound was prepared as in Example 210 Steps E-G, substituting(7-chloro-1-naphthyl) trifluoromethanesulfonate for1-bromo-2-(trifluoromethyl)benzene in step E and also substitutingprop-2-enoyl prop-2-enoate for acryloyl chloride in step G. ESI MS m/z586.1 [M+H]⁺.

Example 2542-[4-[7-(5-fluoro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile

Title compound was prepared as in Example 210 Steps E-G, substituting1-bromo-5-fluoronaphthalene for 1-bromo-2-(trifluoromethyl)benzene instep E and also substituting prop-2-enoyl prop-2-enoate for acryloylchloride in step G. ESI MS m/z 570.3 [M+H]⁺.

Example 2552-[4-[7-(7-methoxy-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile

Step A: (7-methoxy-3,4-dihydronaphthalen-1-yl) trifluoromethanesulfonate

To the solution of 7-methoxytetralin-1-one (1 g, 5.67 mmol) and DIEA(2.20 g, 17.0 mmol, 2.97 mL) in DCM (15 mL) was added Tf₂O (2.40 g, 8.51mmol, 1.40 mL) dropwise, then the mixture was stirred at 20° C. for 12hours. The reaction mixture was concentrated under vacuum. The residuewas purified by silica gel chromatography (PE:EtOAc from 1:0 to 100:1)to give (7-methoxy-3,4-dihydronaphthalen-1-yl) trifluoromethanesulfonate(1.7 g, 5.24 mmol, 92.3% yield, 95.0% purity) as yellow oil. ¹H NMR (400MHz, chloroform-d) 6=7.06 (d, J=8.4 Hz, 1H), 6.75 (dd, J=2.4, 8.4 Hz,1H), 6.66 (d, J=2.4 Hz, 1H), 6.45 (s, 1H), 3.80 (s, 3H), 3.04-2.96 (m,2H), 2.68 (t, J=8.4 Hz, 2H).

Step 2

(7-methoxy-1-naphthyl) trifluoromethanesulfonate: A mixture of(7-methoxy-3,4-dihydronaphthalen-1-yl) trifluoromethanesulfonate (1.7 g,5.51 mmol) and DDQ (2.50 g, 11.0 mmol) in dioxane (30 mL) was stirred at105° C. for 12 hours. The reaction mixture was concentrated undervacuum. The residue was purified by silica gel chromatography (PE:EtOAcfrom 1:0 to 50:1) to give (7-methoxy-1-naphthyl)trifluoromethanesulfonate (1.41 g, 4.14 mmol, 75.1% yield, 90.0% purity)as a colourless oil. ¹H NMR (400 MHz, chloroform-d) 6=7.84 (d, J=9.2 Hz,1H), 7.78 (d, J=8.8 Hz, 1H), 7.65 (d, J=2.4 Hz, 1H), 7.24-7.21 (m, 2H),7.15 (d, J=2.4 Hz, 1H), 3.94 (s, 3H).

Title compound was prepared as in Example 210 Steps E-G, substituting(7-methoxy-1-naphthyl) trifluoromethanesulfonate for1-bromo-2-(trifluoromethyl)benzene in step E and also substitutingprop-2-enoyl prop-2-enoate for acryloyl chloride in step G. ESI MS m/z582.4 [M+H]⁺.

Example 2561-(2-(methoxymethyl)-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Step A: Benzyl4-(4-(tert-butoxycarbonyl)-3-(methoxymethyl)piperazin-1-yl)-2-chloro-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate

A solution of tert-butyl 2-(methoxymethyl)piperazine-1-carboxylate(0.715 g, 3.10 mmol) in N,N-dimethylacetamide (3 ml) was cooled on anice bath with stirring and solid benzyl2,4-dichloro-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate (1.00g, 2.96 mmol) was added in small portions, followed by DIPEA (0.57 mL,3.25 mmol, 1.1 eq.). The resulting solution was allowed to warm up tor.t. over 1 hour, and then divided between water (15 mL) and MTBE (50mL). The organic layer was washed with water (2×10 mL), brine (10 mL),dried over Na₂SO₄ and evaporated in vacuo to give a yellow solid (1.54g, 98%). ES+APCI MS m/z 532.3, [M+H]⁺.

Step B: Benzyl4-(4-(tert-butoxycarbonyl)-3-(methoxymethyl)piperazin-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate

A mixture of crude benzyl4-(4-(tert-butoxycarbonyl)-3-(methoxymethyl)piperazin-1-yl)-2-chloro-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate(500 mg, 0.940 mmol), (S)-(1-methylpyrrolidin-2-yl)methanol (216 mg,1.88 mmol), Cs₂CO₃ (612 mg, 1.88 mmol) and dioxane (0.5 mL) was flushedwith nitrogen. The vial was capped and stirred at 120° C. overnight. Thereaction mixture was cooled, divided between EtOAc (20 mL) and water (10mL), the organic layer was washed with water and brine (5 mL each),dried over Na₂SO₄ and evaporated in vacuo. The compound was purified bysilica gel chromatography, Redisep 40 g, eluting with 4 to 10%MeOH/DCM+0.2% NH₄OH to give a yellow solid (197 mg, 34%). ES+APCI MS m/z611.4 [M+H]⁺.

Step C: Tert-butyl2-(methoxymethyl)-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate

A mixture of benzyl4-(4-(tert-butoxycarbonyl)-3-(methoxymethyl)piperazin-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate(197 mg, 0.323 mmol), methanol (10 mL) and palladium on carbon (10 mg,5%, Degussa type E101 NO/W) was degassed and stirred under hydrogenatmosphere (balloon) for 1 hour. The reaction mixture was filteredthrough Celite (2 mL), washed with MeOH (3×3 mL), evaporated in vacuo,and dried by evaporation with toluene in vacuo and under high vacuum togive a colorless solid (150 mg, 98%). ES+APCI MS m/z 477.2 [M+H]⁺.

Step D: Tert-butyl2-(methoxymethyl)-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate

A mixture of tert-butyl2-(methoxymethyl)-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido-[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(150 mg, 0.315 mmol), Cs₂CO₃ (308 mg, 0.944 mmol), dioxane (1 mL),1-iodonaphthalene (0.0689 ml, 0.472 mmol) andmethanesulfonato(2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl)(2-amino-1,1′-biphenyl-2-yl)palladium(II)(26.3 mg, 0.0315 mmol) (RuPhos-Pd-G3) was purged with nitrogen, theflask was capped and stirred at 70° C. overnight. The reaction mixturewas cooled, divided between EtOAc (15 mL) and water (5 mL), the organiclayer was washed with water and brine (5 mL each), dried over Na₂SO₄ andevaporated in vacuo. The compound was purified by silica gelchromatography, Redisep 40 g, using 4 to 10% MeOH+0.5% NH₄OH as eluentto give a colorless solid, 131 mg. ES+APCI MS m/z 603.3 [M+H]⁺.

Step E:1-(2-(methoxymethyl)-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Tert-butyl2-(methoxymethyl)-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(130 mg, 0.2157 mmol) was dissolved in 1M trifluoroacetic acid in DCM,and the resulted solution was allowed to stay at r.t. for 1 h. Thereaction mixture was divided between 2M Na₂CO₃ (5 mL) and DCM (15 mL),and the organic layer was evaporated in vacuo. The solid residue wasdissolved in DCM (5 mL), cooled on ice-EtOH—CO₂ bath with stirring to−30° C. and triethylamine (0.09 ml, 0.64 mmol) was added, followed byacryloyl chloride (0.035 ml, 0.43 mmol). After 1 min at −30° C. thereaction mixture was quenched with NH₄OH (0.05 mL) and evaporated invacuo and dried under high vacuum. The residue was dissolved in DCM (5mL), filtered through a cotton plug and purified by silica gelchromatography, Redisep 40 g, eluting with 5 to 10% MeOH/DCM+0.25% NH₄OHto give a colorless solid (19.6 mg, 16%). ES+APCI MS m/z 557.3, [M+H]⁺.

Example 2572-(1-acryloyl-4-(2-(((S)-1-(cyclopropylmethyl)pyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

Step A: benzyl2-(cyanomethyl)-4-(2-(((S)-1-(cyclopropylmethyl)pyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate

In a conical bottom vial, a solution of benzyl4-(2-chloro-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate(200 mg, 0.362 mmol) in dioxane (3616 μl, 0.362 mmol) was sparged withArgon for 5 minutes. (S)-(1-(cyclopropylmethyl)pyrrolidin-2-yl)methanol(168 mg, 1.08 mmol), Cs2CO3 (353 mg, 1.08 mmol), Rhuphos Pd G3 (30.2 mg,0.0362 mmol) were sequentially added under Argon and sparged for anadditional 5 minutes. The reaction mixture was capped and heated at 100°C. for 1 hour. LC/MS showed reaction completion. EtOAc was added andwashed with brine (2×). The combined organics were dried over Na2SO4 andconcentrated in vacuo. The concentrate was purified by flashchromatography eluting with 0-20% DCM/MeOH+2% NH₄OH. All fractionscontaining clean desired product were combined and concentrated to givebenzyl2-(cyanomethyl)-4-(2-(((S)-1-(cyclopropylmethyl)pyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(90 mg, 0.134 mmol, 37.0% yield). ES+APCI MS m/z 672.4 [M+H].

Step B:2-(4-(2-(((S)-1-(cyclopropylmethylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-ylacetonitrile

A solution of benzyl2-(cyanomethyl)-4-(2-(((S)-1-(cyclopropylmethyl)pyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(90 mg, 0.13 mmol) in EtOH (1340 μl, 0.13 mmol) and THF (1340 μl, 0.13mmol) was purged with N₂ for 5 min. To this solution was added Palladium(36 mg, 0.033 mmol) (Degussa Type, 10 wt %, 50% H₂O), and wasimmediately capped and purged with N2 for an additional 5 min. Thesolution was then stirred under H2 introduced via vacuum followed byballoon pressure. The mixture was then stirred at ambient temperaturefor 1 hour. LC/MS showed desired product. The mixture was diluted withMeOH and filtered through packed celite. The filtrate was thenconcentrated in vacuo to provide2-(4-(2-(((S)-1-(cyclopropylmethyl)pyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile(71 mg, 0.13 mmol, 99% yield). ES+APCI MS m/z 538.3 [M+H].

Step C:2-(1-acryloyl-4-(2-(((S)-1-(cyclopropylmethyl)pyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

To a suspension of2-(4-(2-(((S)-1-(cyclopropylmethyl)pyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile(71 mg, 0.132 mmol) in dichloromethane (1320 μl, 0.132 mmol) at ambienttemperature was added Acryloyl Chloride (10.7 μl, 0.132 mmol) followedby Hunig's base (46.1 μl, 0.264 mmol). The reaction was then stirred atambient temperature for 1 hour. LC/MS showed reaction completion. Thereaction mixture was concentrated in vacuo. The concentrate wasresuspended in a 60:40 mixture of ACN:H2O and purified on the Gilson(prep HPLC) eluting with 5->95% ACN/0.1% TFA in water/0.1% TFA.Fractions containing product were combined and free based with saturatedbicarb and the organics extracted with DCM. The organics were dried overMgSO4 and concentrated in vacuo to give2-(1-acryloyl-4-(2-(((S)-1-(cyclopropylmethyl)pyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile(15.7 mg, 0.0265 mmol, 20.1% yield). ES+APCI MS m/z 592.4[M+H]⁺.

Example 2582-[4-[7-(1-isoquinolyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile

Title compound was prepared as in Example 210 Steps E-G, substituting1-bromoisoquinoline for 1-bromo-2-(trifluoromethyl)benzene in step E andalso substituting prop-2-enoyl prop-2-enoate for acryloyl chloride instep G. ESI MS m/z 553.3 [M+H]⁺.

Example 2592-[4-[7-(6-fluoro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile

Step A: (6-fluoro-1-naphthyl) trifluoromethanesulfonate

To a solution of 6-fluoronaphthalen-1-ol (0.10 g, 617 umol) and DIEA(159 mg, 1.23 mmol, 215 uL) in dichloromethane (3 mL) was addedtrifluoromethylsulfonyl trifluoromethanesulfonate (191 mg, 678 umol, 112uL) at 0° C. After stirred at 0° C. for 1 hour, the mixture was dilutedwith water (5 mL) and extracted with dichloromethane (3×5 mL). Theorganic layers were washed with brine (1×5 mL), dried over Na₂SO₄,filtered and concentrated under vacuum. The residue was purified bycolumn chromatography (SiO₂, petroleum ether/ethyl acetate=3/1) to give(6-fluoro-1-naphthyl) trifluoromethanesulfonate (0.17 g, 543 umol, 88.1%yield) as a colourless oil. ¹H NMR (400 MHz, chloroform-d) 6=8.10 (dd,J=5.2, 8.8 Hz, 1H), 7.83 (d, J=8.4 Hz, 1H), 7.58-7.50 (m, 2H), 7.48-7.40(m, 2H).

Title compound was prepared as in Example 210 Steps E-G, substituting1(6-fluoro-1-naphthyl) trifluoromethanesulfonate for1-bromo-2-(trifluoromethyl)benzene in step E and also substitutingprop-2-enoyl prop-2-enoate for acryloyl chloride in step G. ESI MS m/z570.3 [M+H]⁺.

Example 2602-[4-[7-(4-isoquinolyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile

Title compound was prepared as in Example 210 Steps E-G, substituting4-bromoisoquinoline for 1-bromo-2-(trifluoromethyl)benzene in step E andalso substituting prop-2-enoyl prop-2-enoate for acryloyl chloride instep G. ESI MS m/z 553.1 [M+H]⁺.

Example 2612-[1-(2-methylprop-2-enoyl)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile

Title compound was prepared as in Example 210 Steps E-G, substituting1-bromonaphthalene for 1-bromo-2-(trifluoromethyl)benzene in step E andalso substituting 2-methylprop-2-enoyl chloride for acryloyl chloride instep G. ESI MS m/z 566.4[M+H]⁺.

Example 2622-[4-[7-(5-isoquinolyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile

Title compound was prepared as in Example 210 Steps E-G, substituting5-bromoisoquinoline for 1-bromo-2-(trifluoromethyl)benzene in step E andalso substituting prop-2-enoyl prop-2-enoate for acryloyl chloride instep G. ESI MS m/z 553.4 [M+H]⁺.

Example 2632-[1-[(E)-but-2-enoyl]-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-7-(1-naphthyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile

Title compound was prepared as in Example 210 Steps E-G, substituting1-bromonaphthalene for 1-bromo-2-(trifluoromethyl)benzene in step E and(E)-but-2-enoyl chloride for acryloyl chloride in step G. ESI MS m/z566.4 [M+H]⁺.

Example 2642-[4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-7-(5-quinolyl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile

Title compound was prepared as in Example 210 Steps E-G, substituting5-bromoquinoline for 1-bromo-2-(trifluoromethyl)benzene in step E andalso substituting prop-2-enoyl prop-2-enoate for acryloyl chloride instep G. ESI MS m/z 553.4 [M+H]⁺.

Example 2652-(1-acryloyl-4-(7-(3-methyl-2-(trifluoromethyl)phenyl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

Title compound was synthesized according to Example 210, Steps E-G using1-bromo-3-methyl-2-(trifluoromethyl)benzene for 1-bromonaphthalene inStep E ES+APCI MS m/z 584.3 [M+H]⁺.

Example 2662-(1-acryloyl-4-(2-(((S)-1-(2-methoxyethyl)pyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

Title compound was synthesized according to Example 147, Steps F-J,using (S)-(1-(2-methoxyethyl)pyrrolidin-2-yl)methanol in place of(S)-(1-methylpyrrolidin-2-yl)methanol in Step F. ES+APCI MS m/z 596.3[M+H]⁺.

Example 2672-((S)-1-acryloyl-4-(2-(((R)-1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

Title compound was synthesized according to Example 234 using(R)-(1-methylpyrrolidin-2-yl)methanol in place of(S)-(1-methylpyrrolidin-2-yl)methanol in Step F. ES+APCI MS m/z 552.3[M+H]⁺.

Example 2682-(1-acryloyl-4-(2-(((2S,4R)-4-methoxy-1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

Title compound was synthesized according to Example 220, (Steps C-G),using tert-butyl(2S,4R)-2-(hydroxymethyl)-4-methoxypyrrolidine-1-carboxylate in place of(2S,4R)-1-(tert-Butoxycarbonyl)-4-fluoro-2-hydroxymethylpyrrolidine inStep C. ES+APCI MS m/z 582.3 [M+H]⁺.

Example 2692-(1-acryloyl-4-(2-(2-(dimethylamino)-2-methylpropoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

The title compound was synthesized following Example 147 substituting2-Dimethylamino-2-methyl-1-propanol for(S)-(1-(cyclopropylmethyl)pyrrolidin-2-yl)methanol in Step F. ES+APCI MSm/z 554.4 [M+H]⁺.

Example 2702-(1-acryloyl-4-(2-(((R)-4-methylmorpholin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

Title compound was synthesized according to Example 147, Steps F-J,using (R)—N-Boc-2-hydroxymethylmorpholine in place of(S)-(1-methylpyrrolidin-2-yl)methanol in Step F. ES+APCI MS m/z 568.3[M+H]⁺.

Example 2712-(1-acryloyl-4-(2-(((S)-4-methylmorpholin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

Title compound was synthesized according to Example 147, Steps F-J,using (S)—N-Boc-2-hydroxymethylmorpholine in place of(S)-(1-methylpyrrolidin-2-yl)methanol in Step F. ES+APCI MS m/z 568.3[M+H]⁺.

Example 2722-(1-acryloyl-4-(2-(((S)-4-methylmorpholin-3-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

Title compound was synthesized according to Example 147, Steps F-J,using tert-butyl (R)-3-(hydroxymethyl)morpholine-4-carboxylate in placeof (S)-(1-methylpyrrolidin-2-yl)methanol in Step F. ES+APCI MS m/z 568.3[M+H]⁺.

Example 2732-(1-acryloyl-4-(2-(((R)-4-methylmorpholin-3-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

Title compound was synthesized according to Example 147, Steps F-J,using tert-butyl (S)-3-(hydroxymethyl)morpholine-4-carboxylate in placeof (S)-(1-methylpyrrolidin-2-yl)methanol in Step F. ES+APCI MS m/z 568.3[M+H]⁺.

Example 2742-((S)-1-acryloyl-4-(7-(3-fluoro-2-(trifluoromethyl)phenyl)-2-(((R)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

Title compound was synthesized according to Example 234, Steps G-J using(R)-(1-methylpyrrolidin-2-yl)methanol in place of(S)-(1-methylpyrrolidin-2-yl)methanol in Step F and1-bromo-3-fluoro-2-(trifluoromethyl)benzene for 1-bromonaphthalene inStep H ES+APCI MS m/z 588.3 [M+H]⁺.

Example 2752-(1-acryloyl-4-(7-(2-fluoro-6-(trifluoromethyl)phenyl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

Title compound was synthesized according to Example 210, Steps E-G using2-bromo-1-fluoro-3-(trifluoromethyl)benzene for 1-bromonaphthalene inStep E. ES+APCI MS m/z 588.3 [M+H]⁺.

Example 2762-(1-acryloyl-4-(7-(4-fluoro-2-(trifluoromethyl)phenyl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

Title compound was synthesized according to Example 210, Steps E-G using1-bromo-4-fluoro-2-(trifluoromethyl)benzene for 1-bromonaphthalene inStep E. ES+APCI MS m/z 588.3 [M+H]⁺.

Example 2772-(1-acryloyl-4-(7-(3-chloro-2-(trifluoromethyl)phenyl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

Title compound was synthesized according to Example 210, Steps E-G using1-bromo-3-chloro-2-(trifluoromethyl)benzene for 1-bromonaphthalene inStep E and THE in place EtOH/THF in Step F. ES+APCI MS m/z 604.3 [M+H]⁺.

Example 2782-(1-acryloyl-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(quinolin-4-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

Title compound was prepared as in Example 210 Steps E-G, substituting4-bromoquinoline for 1-bromo-2-(trifluoromethyl)benzene in step E andalso substituting prop-2-enoyl prop-2-enoate for acryloyl chloride instep G.

Example 2792-(1-acryloyl-4-(2-(2-(dimethylamino)ethoxy)-7-(2-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

Title compound was prepared as in Example 210, substituting N,N-dimethyl-ethanolamine for (2S)-1-Ethyl-2-pyrrolidinyl]methanol in stepC and also substituting prop-2-enoyl prop-2-enoate for acryloyl chloridein step G.

Example 2802-(4-(2-(3-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)propoxy)-7-(2-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-acryloylpiperazin-2-yl)acetonitrile

Title compound was prepared as in Example 210, substituting3-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)propan-1-ol for(2S)-1-Ethyl-2-pyrrolidinyl]methanol in step C and also substitutingprop-2-enoyl prop-2-enoate for acryloyl chloride in step G.

Example 2812-(1-acryloyl-4-(2-(((R)-1-methylpyrrolidin-3-yl)methoxy)-7-(2-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

Title compound was prepared as in Example 210, substituting(R)-(1-methylpyrrolidin-3-yl)methanol for(2S)-1-Ethyl-2-pyrrolidinyl]methanol in step C and also substitutingprop-2-enoyl prop-2-enoate for acryloyl chloride in step G.

Example 2822-(1-(3-methylbut-2-enoyl)-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

Title compound was prepared as in Example 210, substituting1-bromonaphthalene for 1-bromo-2-(trifluoromethyl)benzene in step E and3-methylbut-2-enoyl chloride for acryloyl chloride in step G.

Example 2832-(1-acryloyl-4-(2-(((R)-1-methylpyrrolidin-2-yl)methoxy)-7-(2-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

Title compound was prepared as in Example 210, substituting(2R)-1-Ethyl-2-pyrrolidinyl]methanol for(2S)-1-Ethyl-2-pyrrolidinyl]methanol in step C and also substitutingprop-2-enoyl prop-2-enoate for acryloyl chloride in step G.

Example 2842-(1-acryloyl-4-(2-(2-(diethylamino)ethoxy)-7-(2-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

Title compound was prepared as in Example 210, substituting N,N-diethyl-ethanolamine for (2S)-1-Ethyl-2-pyrrolidinyl]methanol in stepC and also substituting prop-2-enoyl prop-2-enoate for acryloyl chloridein step G.

Example A KRas G12C Modification Assay

This Example illustrates that exemplary compounds of the presentinvention covalently bind to KRas G12C using a LCMS assay to detect acovalent adduct of the exemplary compound and KRAS G12C.

The protein concentration of GDP-loaded K-Ras (1-169) G12C, C51S, C80L,C118S and GTP-loaded K-Ras (1-169) G12C, C51S, C80L, C118S, Q61H wasadjusted to 2 μM in K-Ras Assay Buffer (25 mM HEPES, 150 mM NaCl, 5 mMMgCl2, and 10 mM Octyl 0-glucopyranoside at pH 7.5). A 10 μL aliquot ofeach protein solution was then transferred to a 384 well microtiterplate. Initial compound stocks were generated at fifty times theirdesired final assay concentration in DMSO.

Exemplary compounds of Formula (I) were diluted 25-fold into K-Ras AssayBuffer to a final of two times their final concentration. A 10 μLaliquot of each diluted compound solution was then added to each of theprotein solutions in the microtiter plate to initiate reaction. Typicalfinal compound concentrations were 3.0, 5.0 and 25.0 μM. At each timepoint, the reactions were quenched with 20 μL of a 25 mM acetic acidsolution. Usual assay endpoints were 15, 180 and 1440 minutes. Once allreactions were quenched, the plates were heat sealed and the sampleswere injected into a LC/MS system for data acquisition.

Data collection took place on an Agilent 6520 Q-TOF Accurate MassSpectrometer. Samples were injected in their liquid phase onto a C-3reverse phase column to remove assay buffer and prepare the samples formass spectrometer. The proteins were eluted from the column using anacetonitrile gradient and fed directly into the mass analyzer. Initialraw data analysis took place in Agilent MassHunter software immediatelypost data acquisition.

Raw data analysis of the intact protein was exclusively a deconvolutionof the multiple charge states of each protein in solution using amaximum entropy deconvolution provided in Mass Hunter. To minimizecomplexity, only the data over limited mass ranges were considered foranalysis, with a minimum of one Dalton mass step intervals. The heightsof all masses identified during raw data analysis were exported to befurther analyzed in Spotfire® data analysis software.

Final data analysis was a multistep process in the Spotfire® dataanalysis software package. Briefly, each protein mass was calculated asa percent of the total signal of that sample, that percentage was thennormalized to the percentage of signal of the protein in the absence ofreactive compounds. Those normalized signals were reported as normalizedpercent of control (POC). An increased POC value indicates a compoundthat displays a higher degree of modification at a given conditioncompared to other compounds under the same conditions. The results forexemplary compounds of Formula (I) tested at 5 μM concentration for 3hours are shown in Table 1. Key: “A”≤25% POC; “B”>25% POC≤50% POC;“C”>50% POC and ND=not determined.

TABLE 1 Inhibition of KRas G12C Activity by Exemplary Compounds ofFormula (I) Example No. POC 1 B 2 A 3 A 4 A 5 A 6 B 7 A 8 B 9 C 10 C 11C 12 C 13 C 14 C 15 C 16 C 17 B 18 C 19 C 20 C 21 C 22 C 23 C 24 A 25 A26 C 27 C 28 C 29 C 30 A 31 B 32 C 33 B 34 A 35 C 36 C 37 C 38 C 39 C 40C 41 A 42 A 43 C 44 C 45 A 46 A 47 C 48 C 49 B 50 C 51 A 52 C 53 C 54 A55 C 56 C 57 C 58 C 59 C 60 C 61 C 62 C 63 C 64 C 65 C 66 C 67 C 68 A 69A 70 C 71 A 72 C 73 C 74 C 75 C 76 C 77 C 78 C 79 A 80 C 81 C 82 C 83 C84 A 85 C 86 A 87 A 88 C 89 C 90 C 91 A 92 C 93 C 94 A 95 A 96 A 97 C 98C 99 C 100 C 101 C 102 C 103 C 104 C 105 B 106 A 107 C 108 C 109 C 110 C111 C 112 A 113 C 114 B 115 C 116 C 117 C 118 A 119 B 120 C 121 C 122 C123 A 124 C 125 A 126 C 127 C 128 C 129 C 130 C 131 C 132 C 133 C 134 C135 C 136 C 137 C 138 C 139 C 140 C 141 C 142 C 143 C 144 C 145 C 146 B147 C 148 C 149 B 150 C 151 B 152 C 153 C 154 C 155 C 156 C 157 C 158 C159 C 160 C 161 C 162 B 163 C 164 C 165 C 166 B 167 B 168 C 169 C 170 C171 C 172 C 173 C 174 C 175 C 176 C 177 C 178 C 179 C 180 C 181 C 182 C183 C 184 C 185 C 186 B 187 C 188 C 189 C 190 C 191 C 192 C 193 C 194 C195 C 196 C 197 C 198 C 199 C 200 C 201 B 202 C 203 C 204 C 205 C 206 C207 C 208 C 209 C 210 C 211 C 212 C 213 C 214 C 215 C 216 C 217 C 218 C219 C 220 C 221 C 222 C 223 C 224 C 225 C 226 C 227 A 228 C 229 C 230 C231 C 232 C 233 C 234 C 235 C 236 C 237 C 238 C 239 C 240 C 241 C 242 C243 C 244 C 245 C 246 C 247 C 248 C 249 C 250 C 251 C 252 ND 253 ND 254ND 255 ND 256 C 257 C 258 C 259 C 260 C 261 A 262 A 263 C 264 C 265 C266 C 267 C 268 C 269 C 270 C 271 C 272 C 273 C 274 C 275 C 276 C 277 C

Example B Inhibition of KRas G12C-Dependent Cell Growth

This Example illustrates that exemplary compounds of the presentinvention inhibit the growth of tumor cell lines that express KRas G12C.

The cellular inhibition of KRAs G12C by exemplary compounds of thepresent invention was determined by measuring the amount of a downstreammarker of KRas activity, phosphorylated ERK (“Phospho-ERK”).

NCI-H358 cells (ATCC CRL-5807) express KRas G12C and were grown in RPMImedium supplemented with 10% fetal bovine serum, penicillin/streptomycinand 10 mM HEPES. Cells were plated in poly-D-Lysine coated 96-wellplates at a concentration of 50,000 cells/well and allowed to attach for8-12 hours. Diluted compounds were then added at a final concentrationof 0.5% DMSO. After 3 hours, the medium was removed, 150 μL of 4%formaldehyde was added and the plates were incubated for 20 minutes. Theplates were washed with PBS, and permeabilized using 150 μL of ice cold100% methanol for 10 minutes. Non-specific antibody binding to theplates was blocked using 100 μL Licor Blocking Buffer (Li-CorBiotechnology, Lincoln Nebr.) for 1 hour at room temperature. Positivecontrol samples and samples lacking cells were parallel processed withtest samples as standards.

The amount Phospho-ERK was determined using an antibody specific for thephosphorylated form of ERK and compared to the amount of GAPDH. Primaryantibodies used for detection were added as follows: Phospho-ERK (CellSignaling cs9101) diluted 1:500 and GAPDH (Millipore MAB374) diluted1:5000 in Licor block+0.05% Tween 20. The plates were incubated for 2hours at room temperature. The plates were washed with PBS+0.05% Tween20.

Secondary antibodies used to visualize primary antibodies were added asfollows: Anti-rabbit-680 diluted 1:1000 and Anti-mouse-800 diluted1:1000 in Licor Block+0.050 Tween 20 and incubated for 1 hour at roomtemperature. The plates were washed with PBS+0.05% o Tween 20. A100 Laliquot of PBS was added to each well and the plates were read on aLICOR AERIUS plate reader.

The pERK(Thr202/Tyr204) signal was normalized with the GAPDH signal andpercent of DMSO control values were calculated. IC₅₀ values weregenerated using a 4 parameter fit of the dose response curve. Theresults for exemplary compounds of Formula (I) are shown in Table 2.Key: “A”≥0.001-≤1 μM; “B”>1 M and ND=not determined.

TABLE 2 Inhibition of KRas G12C-mediated Cell Proliferation by ExemplaryCompounds Example No. IC₅₀ 1 B 2 B 3 B 4 B 5 B 6 B 7 B 8 B 9 B 10 B 11 A12 B 13 B 14 B 15 B 16 B 17 B 18 B 19 A 20 B 21 A 22 B 23 B 24 B 25 B 26B 27 A 28 A 29 B 30 B 31 B 32 A 33 B 34 B 35 B 36 B 37 B 38 A 39 A 40 A41 B 42 B 43 B 44 B 45 B 46 B 47 B 48 B 49 B 50 B 51 B 52 A 53 B 54 B 55A 56 A 57 B 58 B 59 B 60 B 61 B 62 B 63 B 64 A 65 B 66 B 67 A 68 B 69 B70 B 71 B 72 A 73 B 74 A 75 A 76 B 77 A 78 B 79 B 80 B 81 B 82 A 83 B 84B 85 B 86 B 87 B 88 A 89 A 90 A 91 B 92 A 93 B 94 B 95 B 96 B 97 A 98 B99 B 100 B 101 A 102 A 103 A 104 A 105 B 106 B 107 B 108 A 109 B 110 A111 A 112 B 113 B 114 B 115 A 116 A 117 B 118 B 119 B 120 A 121 B 122 B123 B 124 B 125 B 126 B 127 A 128 B 129 A 130 A 131 A 132 A 133 B 134 B135 A 136 B 137 B 138 B 139 B 140 B 141 B 142 B 143 B 144 A 145 A 146 B147 A 148 A 149 A 150 A 151 B 152 A 153 A 154 A 155 A 156 A 157 B 158 B159 B 160 B 161 B 162 B 163 B 164 B 165 B 166 B 167 B 168 B 169 A 170 A171 B 172 B 173 B 174 B 175 A 176 A 177 A 178 A 179 A 180 A 181 B 182 A183 A 184 B 185 A 186 B 187 A 188 A 189 B 190 A 191 B 192 A 193 A 194 B195 B 196 A 197 A 198 B 199 B 200 B 201 B 202 A 203 A 204 B 205 B 206 A207 B 208 B 209 B 210 A 211 A 212 A 213 B 214 B 215 B 216 B 217 B 218 A219 B 220 A 221 A 222 A 223 A 224 A 225 A 226 A 227 A 228 A 229 A 230 A231 A 232 B 233 A 234 A 235 A 236 A 237 A 238 A 239 B 240 B 241 B 242 A243 A 244 A 245 A 246 A 247 B 248 B 249 A 250 B 251 A 252 ND 253 ND 254ND 255 ND 256 B 257 A 258 B 259 A 260 A 261 B 262 B 263 A 264 B 265 A266 A 267 A 268 A 269 A 270 A 271 A 272 A 273 B 274 A 275 A 276 A 277 A

While the invention has been described in connection with specificembodiments thereof, it will be understood that it is capable of furthermodifications and this application is intended to cover any variations,uses, or adaptations of the invention following, in general, theprinciples of the invention and including such departures from thepresent disclosure as come within known or customary practice within theart to which the invention pertains and as may be applied to theessential features hereinbefore set forth, and as follows in the scopeof the appended claims.

1. A compound of formula (I):

or a pharmaceutically acceptable salt thereof: wherein: X is a 4-12membered saturated or partially saturated monocyclic, bridged orspirocyclic ring, wherein the saturated or partially saturatedmonocyclic ring is optionally substituted with one or more R⁸; Y is abond, O, S or NR⁵; R¹ is —C(O)C(R^(A))

C(R^(B))_(p) or —SO₂C(R^(A))

C(R^(B))_(p); R² is hydrogen, alkyl, hydroxyalkyl, dihydroxyalkyl,alkylaminylalkyl, dialkylaminylalkyl, —Z—NR⁵R¹⁰, heterocyclyl,heterocyclylalkyl, aryl, heteroaryl, or heteroarylalkyl, wherein each ofthe Z, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, andheteroarylalkyl may be optionally substituted with one or more R⁹; Z isC1-C4 alkylene; each R³ is independently C1-C3 alkyl, oxo, or haloalkyl;L is a bond, —C(O)—, or C1-C3 alkylene; R⁴ is hydrogen, cycloalkyl,heterocyclyl, aryl, aralkyl or heteroaryl, wherein each of thecycloalkyl, heterocyclyl, aryl, aralkyl and heteroaryl may be optionallysubstituted with one or more R⁶ or R⁷; each R⁵ is independently hydrogenor C1-C3 alkyl; R⁶ is cycloalkyl, heterocyclyl, heterocyclylalkyl, aryl,or heteroaryl, wherein each of the cycloalkyl, heterocyclyl, aryl, orheteroaryl may be optionally substituted with one or more R⁷; each R⁷ isindependently halogen, hydroxyl, C1-C6 alkyl, cycloalkyl, alkoxy,haloalkyl, amino, cyano, heteroalkyl, hydroxyalkyl or Q-haloalkyl,wherein Q is O or S; R⁸ is oxo, C1-C3 alkyl, C2-C4 alkynyl, heteroalkyl,cyano, —C(O)OR⁵, —C(O)N(R⁵)₂, —N(R⁵)₂, wherein the C1-C3 alkyl may beoptionally substituted with cyano, halogen, —OR⁵, —N(R⁵)₂, orheteroaryl; each R⁹ is independently hydrogen, oxo, acyl, hydroxyl,hydroxyalkyl, cyano, halogen, C1-C6 alkyl, aralkyl, haloalkyl,heteroalkyl, cycloalkyl, heterocyclylalkyl, alkoxy, dialkylaminyl,dialkylamidoalkyl, or dialkylaminylalkyl, wherein the C1-C6 alkyl may beoptionally substituted with cycloalkyl; each R¹⁰ is independentlyhydrogen, acyl, C1-C3 alkyl, heteroalkyl or hydroxyalkyl; R^(A) isabsent, hydrogen, or C1-C3 alkyl; each R^(B) is independently hydrogen,C1-C3 alkyl, alkylaminylalkyl, dialkylaminylalkyl or heterocyclylalkyl;m is zero or an integer between 1 and 2; p is one or two; and wherein,when

is a triple bond then R^(A) is absent, R^(B) is present and p equalsone, or when

is a double bond then R^(A) is present, R^(B) is present and p equalstwo, or R^(A), R^(B) and the carbon atoms to which they are attachedform a 5-8 membered partially saturated cycloalkyl optionallysubstituted with one or more R⁷.
 2. The compound of claim 1, whereinR¹—X is:

wherein the piperazinyl ring is optionally substituted with R⁸.
 3. Thecompound of claim 2, wherein R⁸ is —C(O)C(R^(A))

C(R^(B))_(p), wherein

is a triple bond R^(A) is absent, p is one and R^(B) is C1-C3 alkyl, or

is a double bond, R^(A) is hydrogen or C1-C3 alkyl, p is two and eachR^(B) is independently hydrogen, C1-C3 alkyl, dialkylaminylalkyl orheterocyclylalkyl.
 4. The compound of claim 21, wherein R⁸ is—C(O)CH═CH₂.
 5. The compound of according to claim 1, wherein Y is O. 6.(canceled)
 7. The compound of claim 1, wherein R² is heterocyclylalkyl.8. The compound of claim 7, wherein the heterocyclyl of theheterocyclylalkyl is independently azetidinyl, methylazetidinyl,difluoroazetidinyl, tetrahydropyran, pyrrolidinyl, methylpyrrolidinyl,diemethylpyrrolidinyl, isopropylpyrrolidinyl,cycloalkylalkylpyrrolidinyl, hydroxypyrrolindinyl, fluoropyrrolidinyl,difluoropyrrolidinyl, methoxyethylpyrrolidinyl,(N-methyl)methoxypyrrolidinyl, piperazinyl, dimethylaminylpyrrolidinyl,morpholinyl, methylmorpholinyl, 1,4-oxazepanyl, piperdinyl,methylpiperidinylacylpiperdinyl, cyanopiperdinyl, cycloalkylpiperdinyl,halopiperdinyl, dihalopiperdinyl, fluoropiperdinyl, difluoropiperdinyl,alkoxypiperdinyl, pyrrolidonyl, piperidinonyl,thiomorpholinyl-1,1-dioxide, 3-azabicyclo[3.1.0]hexanyl,oxa-5-azabicyclo[2.2.1]heptan-5-yl, orazabicyclo[2.2.1]heptan-2-yl. 9.(canceled)
 10. (canceled)
 11. The compound of claim 61, wherein R² is—ZR⁵R¹⁰.
 12. (canceled)
 13. (canceled)
 14. (canceled)
 15. (canceled) 16.(canceled)
 17. (canceled)
 18. The compound according to claim 1, whereinR⁴ is aryl optionally substituted with one or more R⁷.
 19. The compoundof claim 18, wherein the aryl is selected from the group consisting ofphenyl and naphthyl optionally substituted with one or more R⁷. 20.(canceled)
 21. (canceled)
 22. The compound according to claim 1, whereinR⁴ is heteroaryl.
 23. The compound of claim 22, wherein the heteroarylis pyridinyl, indolyl, indazolyl, quinolinyl, isoquinolinyl orbenzo[d]thiazolyl.
 24. (canceled)
 25. (canceled)
 26. (canceled) 27.(canceled)
 28. (canceled)
 29. (canceled)
 30. (canceled)
 31. (canceled)32. (canceled)
 33. (canceled)
 34. The compound according to claim 1,wherein R⁴ is aralkyl optionally substituted with one or more R⁷. 35.(canceled)
 36. (canceled)
 37. (canceled)
 38. (canceled)
 39. The compoundaccording to claim 1, wherein L is a bond.
 40. The compound according toclaim 1, wherein R⁸ is heteroalkyl, C2-C4 alkynyl, or C1-C3alkyloptionally substituted with —OR⁵, cyano or heteroaryl.
 41. (canceled)42. (canceled)
 43. (canceled)
 44. The compound of claim 40, wherein R⁸is C1-C3 alkyl substituted with —OR⁵.
 45. The compound of claim 40,wherein R⁸ is oxazolylmethyl.
 46. (canceled)
 47. (canceled) 48.(canceled)
 49. (canceled)
 50. (canceled)
 51. (canceled)
 52. The compoundof claim 1, wherein the compound is of Formula I-B:

where the piperidinyl ring is optionally substituted with R⁸, and R¹,R³, R⁴, R⁹, L and m are as defined in claim
 1. 53. The compound of claim52, wherein R² is heterocyclylalkyl.
 54. The compound of claim 53,wherein the heterocyclyl portion of the heterocyclylalkyl ispyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, 1,4-oxazepanyl,thiomorpholinyl-1,1-dioxide, 3-azabicyclo[3.1.0]hexanyl,2-oxa-5-azabicyclo[2.2.1]heptan-5-yl, or azabicyclo[2.2.1]heptan-2-yl,each optionally substituted with one or more R⁹.
 55. (canceled)
 56. Thecompound of claim 44, wherein R⁸ is heteroalkyl, C2-C4 alkynyl, orC1-C3alkyl optionally substituted or —OR⁵, cyano or heteroaryl.
 57. Thecompound according to claim 52, wherein L is a bond and R⁴ is aryl orheteroaryl, each optionally substituted with one or more R⁶ or R⁷. 58.(canceled)
 59. The compound of claim 1, wherein R¹—X is:

wherein A and B are a spirocyclic ring system, wherein A and B are thesame or different and independently represent a 4-6 membered saturatedring system optionally substituted with one or more R⁸.
 60. (canceled)61. (canceled)
 62. (canceled)
 63. (canceled)
 64. (canceled)
 65. Thecompound according to claim 59, wherein R⁴ is aryl optionallysubstituted with one or more R⁷.
 66. The compound of claim 65, whereinthe aryl is selected from the group consisting of phenyl and naphthyloptionally substituted with one or more R⁷.
 67. (canceled) 68.(canceled)
 69. (canceled)
 70. (canceled)
 71. (canceled)
 72. (canceled)73. (canceled)
 74. (canceled)
 75. (canceled)
 76. (canceled) 77.(canceled)
 78. (canceled)
 79. The compound according to claim 59,wherein L is a bond.
 80. The compound according to claim 59, wherein thespirocyclic ring system formed by A and B are selected from the groupconsisting of:


81. (canceled)
 82. (canceled)
 83. (canceled)
 84. The compound of claim1, wherein R⁴ is phenyl or naphthyl, wherein each of the phenyl andnaphthyl are optionally substituted with one or more R⁹.
 85. Thecompound of claim 1, wherein the compound is selected from the groupconsisting of:


86. A pharmaceutical composition, comprising a therapeutically effectiveamount of a compound according to any claim 1, and a pharmaceuticallyacceptable excipient.
 87. A method for inhibiting KRas G12C activity ina cell, comprising contacting the cell in which inhibition of KRas G12Cactivity is desired with an effective amount of a compound according toclaim 1, pharmaceutically acceptable salts thereof or pharmaceuticalcompositions containing the compound of Formula (I), Formula I-A orFormula I-B, or pharmaceutically acceptable salt thereof.
 88. A methodfor treating cancer comprising administering to a patient having cancera therapeutically effective amount of a compound according to claim 1 ora pharmaceutically acceptable salt thereof, alone or combined with apharmaceutically acceptable carrier, excipient or diluents. 89.(canceled)
 90. (canceled)
 91. The method of claim 88, wherein the canceris selected from the group consisting of Cardiac: sarcoma (angiosarcoma,fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma,fibroma, lipoma and teratoma; Lung: bronchogenic carcinoma (squamouscell, undifferentiated small cell, undifferentiated large cell,adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma,sarcoma, lymphoma, chondromatous hamartoma, mesothelioma;Gastrointestinal: esophagus (squamous cell carcinoma, adenocarcinoma,leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma,leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma,glucagonoma, gastrinoma, carcinoid tumors, vipoma), small bowel(adenocarcinoma, lymphoma, carcinoid tumors, Kaposi's sarcoma,leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large bowel(adenocarcinoma, tubular adenoma, villous adenoma, hamartoma,leiomyoma); Genitourinary tract: kidney (adenocarcinoma, Wilm's tumor(nephroblastoma), lymphoma, leukemia), bladder and urethra (squamouscell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate(adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonalcarcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cellcarcinoma, fibroma, fibroadenoma, adenomatoid tumors, lipoma); Liver:hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma,angiosarcoma, hepatocellular adenoma, hemangioma; Biliary tract: gallbladder carcinoma, ampullary carcinoma, cholangiocarcinoma; Bone:osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibroushistiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma(reticulum cell sarcoma), multiple myeloma, malignant giant cell tumorchordoma, osteochronfroma (osteocartilaginous exostoses), benignchondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma andgiant cell tumors; Nervous system: skull (osteoma, hemangioma,granuloma, xanthoma, osteitis deformans), meninges (meningioma,meningiosarcoma, gliomatosis), brain (astrocytoma, medulloblastoma,glioma, ependymoma, germinoma (pinealoma), glioblastoma multiform,oligodendroglioma, schwannoma, retinoblastoma, congenital tumors),spinal cord neurofibroma, meningioma, glioma, sarcoma); Gynecological:uterus (endometrial carcinoma (serous cystadenocarcinoma, mucinouscystadenocarcinoma, unclassified carcinoma), granulosa-thecal celltumors, Sertoli-Leydig cell tumors, dysgerminoma, malignant teratoma),vulva (squamous cell carcinoma, intraepithelial carcinoma,adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma,squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma),fallopian tubes (carcinoma); Hematologic: blood (myeloid leukemia (acuteand chronic), acute lymphoblastic leukemia, chronic lymphocyticleukemia, myeloproliferative diseases, multiple myeloma, myelodysplasticsyndrome), Hodgkin's disease, non-Hodgkin's lymphoma (malignantlymphoma); Skin: malignant melanoma, basal cell carcinoma, squamous cellcarcinoma, Kaposi's sarcoma, moles dysplastic nevi, lipoma, angioma,dermatofibroma, keloids, psoriasis; and Adrenal glands: neuroblastoma.92. The method of claim 88, wherein the cancer wherein the cancer is aKRas G12C-associated cancer.
 93. The method of claim 88, wherein thecancer is non-small cell lung cancer.
 94. A method for treating cancerin a patient in need thereof, the method comprising (a) determining thatthe cancer is associated with a KRas G12C mutation (e.g., a KRasG12C-associated cancer); and (b) administering to the patient atherapeutically effective amount of a compound according to claim 1 or apharmaceutically acceptable salt thereof, or a pharmaceuticalcomposition thereof.
 95. (canceled)